JP5374153B2 - (+)-1,4-Dihydro-7-[(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2- Method using thiazolyl) -1,8-naphthyridine-3-carboxylic acid - Google Patents

Abstract

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

Description

  This application is directed to U.S. Patent Application Nos. 11 / 218,387 and 11 / 218,653 (both filed on September 2, 2005) [and currently switched to a US provisional application] And claims priority to U.S. provisional applications 60 / 789,093 and 60 / 788,927 (both filed April 3, 2006) and 60 / 810,285 filed June 1, 2006. To do. All of these applications are incorporated by reference in their entirety.

(1. Field)
Enantiomerically pure (+)-1,4-dihydro-7-[(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl], also known as SNS-595 or AG-7352 A method for treating, preventing or managing cancer, including certain leukemias, by administering -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid Provided in the description. Also provided are doses, dosing schedules and dosages for SNS-595 and its administration.

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

SNS-595 is known for its anti-tumor activity. Treatment of the following cancers with SNS-595 has been proposed in the literature: bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, melanoma, myeloma, nerve Blastoma (ie CNS cancer), ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma, skin cancer, gastric cancer, testicular cancer, thyroid cancer and uterine cancer. Various dosing schedules have been reported, see for example US Patent Application Publication Nos. 2005-0203120; 2005-0215583 and 2006-0025437, all of which are hereby incorporated by reference in their entirety. Incorporated.
There remains a need for safe and effective dosages and regimens for administering SNS-595 in treating, preventing and managing various cancers, including leukemia.

3. (Summary)
SNS-595 is a known cytotoxic agent having utility against various cancers. Described herein are new treatment methods, including treatment of certain leukemias. In addition, unique dosage ranges, formulation schedules and pharmaceutical dosages are described.

  The treatment, prevention or management of cancer using SNS-595, its pharmaceutical composition and unique medication is described. In general, types of cancer that can be treated, prevented, or managed using the methods provided herein include, but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (Including colorectal cancer), esophageal cancer, head and neck cancer, liver cancer, lung cancer (both small and non-small cells), melanoma, myeloma, neuroblastoma (i.e., CNS cancer), 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. Cancer can be recurrent, refractory or resistant to conventional therapy.

  In certain embodiments, cancer includes hematological malignancies including, but not limited to, leukemia, lymphoma (having non-Hodgkin lymphoma), Hodgkin's disease (also referred to as Hodgkin lymphoma) and myeloma. Various forms of leukemia include, but are not limited to, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia. Leukemia can recur, be refractory or resistant. In certain embodiments, the hematological malignancy is promyelocytic leukemia, T cell leukemia or lymphoblastic leukemia.

Further provided are methods of treating, preventing, or managing cancer by administering SNS-595 in a specific manner. In certain embodiments, the method comprises administering to a mammal, from about 1mg / m ² ~150mg / m ² on the basis of body surface area, about ^{1mg / m 2 ~100mg / m 2} , 1mg / m 2 ~75mg / comprising administering a ^{m 2, 15mg / m 2 ~80mg} / m 2 or about 3 mg / m ² doses of SNS-595 in ~24mg / m ^2. 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. Additional dosing and dosing schedules are described in further detail herein below.

  Also provided herein are dosages and regimens for solid cancer. The dose of SNS-595 administered can be as a single dose, such as an IV push (e.g., a single bolus injection) for a period of 10-15 minutes, or over a period of time, e.g., a period of 24 hours (e.g., is Continuous infusion over a period of time or divided boluses over a period of time) and can be delivered as needed, e.g. until the patient experiences stable disease or regression, or the patient experiences disease progression or unacceptable toxicity Repeat until

  In some embodiments, SNS-595 can be administered periodically to the patient. Cycling therapy involves the administration of an active agent for a while followed by a pause for a while, and this continuous administration is repeated. Cycling therapy can reduce the development of resistance to one or more therapies, avoid or reduce one side effect of the therapy, and / or improve the effectiveness of the treatment.

  In another embodiment, SNS-595 is administered in combination with another drug ("second active agent") or another therapy used in conventional methods for treating, preventing, or managing cancer. Or the SNS-595 dosing method described herein can be applied to a combination therapy environment. Second active agents include known small molecules, anti-cancer agents, anti-tumor agents or cytotoxic agents and large molecules (eg, proteins and antibodies), examples of which are provided herein, and stem cells or cord blood. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, immunotherapy, blood transfusion, and combinations thereof.

Thus, in certain embodiments, combinations for the treatment, prevention and management of solid tumors are provided herein. In other embodiments, provided herein are combinations for the treatment, prevention and management of leukemia and lymphoma.
Also provided are pharmaceutical compositions, a single unit dosage form and a dosage regimen comprising SNS-595 and a second (or additional) active agent. Second active agents include specific combinations or “cocktails” of drugs or therapies or both.

(5. Definition)
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All cited patents, applications, published applications and other publications are incorporated by reference in their entirety. In this specification, when there are a plurality of definitions for a term, those in this section prevail unless otherwise specified.

  Enantiomerically pure (+)-1,4-dihydro-7-[(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo as used herein -1- (2-Thiazolyl) -1,8-naphthyridine-3-carboxylic acid is (-)-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 (ie enantiomeric excess). In other words, 1,4-dihydro-7-[(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8- The “(+)” form of naphthyridine-3-carboxylic acid is substantially free of the “(−)” form of the compound and is therefore an enantiomeric excess of the “(−)” form. The term “enantiomerically pure” or “pure enantiomer” means that the compound is greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, 92% It is meant to contain greater than 93%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97% by weight enantiomer.

  As used herein and unless otherwise stated, “enantiomerically pure (+)-1,4-dihydro-7-[(3S, 4S) -3-methoxy-4- (methylamino) -1” The term “-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid” means 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 at most about 20% by weight ( -)-1,4-dihydro-7-[(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8- Naphthyridine-3-carboxylic acid, at least about 90% 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 at most about 10% by weight of (-)-enantiomer, at least about 95% by weight of (+)-1,4-dihydride B-7-[(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid and At most about 5% by weight of (-)-enantiomer, 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 at most about 3% by weight of (−)-enantiomer.

As used herein and unless otherwise specified, the terms “treat”, “treating”, and “treatment” reduce or reduce the severity of symptoms associated with the disease or condition being treated. It means to make it.
The term “prevention” includes inhibition of the symptoms of a particular disease or disorder. In some embodiments, patients with a family history of cancer are candidates for prevention planning. In general, the term “prevent” refers to administering a drug prior to onset of symptoms, particularly to patients at risk for cancer.

  As used herein and unless otherwise specified, the term “manage” refers to preventing a recurrence of a particular disease or disorder in a patient suffering from it, or a patient suffering from a disease or disorder in remission. Increasing the time that remains, reducing patient mortality, and / or maintaining or avoiding the severity of symptoms associated with the disease or condition being managed.

As used herein, a “subject” such as a patient is an animal, typically a mammal including a human.
The term “cancer” as used herein includes, but is not limited to, solid tumors and blood derived tumors. The term “cancer” refers to bladder, bone or blood, brain, breast, neck, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lung, mouth, neck, ovary, pancreas, prostate, It refers to diseases of skin tissue, organs, blood and blood vessels, including but not limited to cancer of the rectum, stomach, testis, throat and uterus.

As used herein, “hematologic malignancy” refers to the body's hematopoietic and immune system—cancer of bone marrow and lymphoid tissues. Such cancers include leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also referred to as Hodgkin lymphoma) and myeloma.
The term “leukemia” refers to a malignant neoplasm of hematopoietic tissue. Leukemias include but are not limited to chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukemia and acute myeloblastic leukemia. Leukemia can be recurrent, refractory or resistant to conventional therapy.

  As used herein, “promyelocytic leukemia” or “acute promyelocytic leukemia” is a deficiency of mature blood cells in cells of the myeloid lineage and an excess of immature cells called promyelocytes. A malignant tumor of the bone marrow. This is usually characterized by the exchange of part of chromosomes 15 and 17.

As used herein, “acute lymphoblastic leukemia”, also known as “acute lymphoblastic leukemia” (ALL), is a malignant disease caused by abnormal growth and development of early non-granular leukocytes or lymphocytes Say.
As used herein, “T-cell leukemia” refers to a disease in which specific cells of the lymphoid system called T lymphocytes or T cells are malignant. T cells are white blood cells that can normally attack virus-infected cells, foreign cells, and cancer cells, and produce substances that modulate the immune response.

The term “relapsed” refers to a situation where there is a return of cancer cells in a patient who has had a remission of cancer after therapy.
The term “refractory or resistant” refers to an environment in which patients have cancer cells that remain in their bodies even after intensive treatment.
As used herein, IC ₅₀ refers to the amount, concentration or dosage of a particular test compound that achieves 50% inhibition of maximal response in an assay that measures such response.

  As used herein and unless otherwise specified, the terms “therapeutically effective amount” and “effective amount” of a compound are intended to provide therapeutic benefit in the treatment, prevention, and / or management of a disease. An amount sufficient to delay or minimize one or more symptoms associated with the disease or disorder being treated. The terms “therapeutically effective amount” and “effective amount” refer to improving overall therapy, reducing or avoiding the symptoms or etiology of a disease or disorder, or enhancing the therapeutic effectiveness of another therapeutic agent. Can be included.

  As used herein and unless otherwise specified, the term “pharmaceutically acceptable salt” includes salts of acidic or basic groups that may be present in the compounds provided herein. , Not limited. Under certain acidic conditions, the compounds can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to produce pharmaceutically acceptable salts of such basic compounds include acetate, benzenesulfonate, benzoate, bicarbonate, hydrogen tartrate, bromide, calcium Edetate, cansylate, carbonate, chloride, bromide, iodide, citrate, dichloride, edetate, edicylate, estrate, esylate, fumarate, glutamate, gluconate, glutamate, glyco Rilarsanylate, hexyl resorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate mascara, napsilate , Nitrate, pantothenate, phosphate / diphosphate, polygalacturonate, salicy Including those that form salts with pharmacologically acceptable anions, including acid salts, stearates, succinates, sulfates, tannates, tartrate, theocrate, triethiodides and pamoates, It is not limited. Under certain basic conditions, the compounds can form base salts with various pharmacologically acceptable cations. Non-limiting examples of such salts include alkali metal or alkaline earth metal salts, and particularly calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

As used herein and unless otherwise specified, the term “hydrate” further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. It means a compound provided herein or a salt thereof.
As used herein and unless otherwise specified, the term “solvate” means a solvate formed by the association of one or more solvent molecules to a compound provided herein. The term “solvate” includes hydrates (eg, monohydrate, dihydrate, trihydrate, tetrahydrate, etc.).

The terms `` co-administration '' and `` in combination with '' refer to two therapeutic agents (e.g., SNS-595 and another anticancer agent or second agent) simultaneously, simultaneously, or sequentially without a specific time limit. Administration). In one embodiment, both agents are present in the cell or the patient's body at the same time or exert their biological or therapeutic effect simultaneously. 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 “adjuvant treatment” refers to any substance that treats, prevents, or manages the adverse effects of SNS-595 treatment.

(6. Detailed explanation)
(6.1 SNS-595)
The compounds for use in the methods and compositions provided herein are enantiomerically pure (+)-1,4-dihydro-7-[(3S, 4S) -3-methoxy-4- ( Methylamino) -1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid, also known as SNS-595 or AG-7352. SNS-595 has the following chemical structure:

In certain embodiments, a pharmaceutically acceptable salt, solvate, hydrate or prodrug of SNS-595 is used in the methods and compositions provided herein.
SNS-595 can be prepared by methods known to those skilled in the art, for example, “Compounds, processes for the preparation reagents and anti-tumor agents” published on October 6, 1998. ) ", For example C-1 of US Pat. No. 5,817,669, and to Chikugi et al. In Japanese Patent Application No. 10-17398, both of which are incorporated by reference in their entirety. Are incorporated herein. Certain exemplary pharmaceutical compositions comprising SNS-595 and methods of using the foregoing are described in US Patent Application Publication Nos. 2005-0203120; 2005-0215583 and 2006-0025437, which All of which are incorporated herein by reference in their entirety.

(6.2 Usage)
Proliferating cells undergo a four-phase cell cycle: G ₁ , S, G ₂ and M. These phases were first identified by observing dividing cells as cells that progressed through DNA synthesis, which became known as the synthetic phase or S phase of the cell cycle and mitosis, and the mitosis of the cell cycle Known as the mitotic or M-phase or S-phase. Between completion and mitosis of DNA synthesis, and the interval to be observed in time during mitosis to the next cycle of DNA synthesis, and the G ₁ and G ₂ phases, respectively. Non-proliferating cells that retain the ability to proliferate under appropriate conditions, there still or G ₀ state, is typically characterized as having exited the cell cycle.

SNS-595 is a cell cycle inhibitor and arrests cells at G ₂ boundary. Without being limited by any particular theory, SNS-595 mediates activation of the DNA-PK pathway, ultimately leading to apoptotic cell death. These events are S phase specific, ie they occur only during the S phase of the cell cycle. Without being limited by a particular theory, treatment with SNS-595 results in an increase in the number of double-stranded DNA breaks that form during the S phase. This damage impedes the ability of the cell to synthesize DNA and increases the time the cell spends in S phase. Once DNA damage is detected in the cell, a marker for apoptosis appears quickly. This rapid onset of apoptosis appears to be p73 dependent, as indicated by a more than 11-fold decrease in SNS-595 sensitivity in p73 null cells compared to p73 containing cells.

As illustrated in FIG. 7, the formation of double-strand breaks is in a dose-dependent manner: i) DNA-PK expression; ii) H2AX phosphorylation; iii) c-Abl phosphorylation; iv) p53 phosphorylation; It activates DNA-PK-mediated repair and apoptotic cell mechanisms including but not limited to: p73 phosphorylation; vi) p21 expression; vii) caspase-9 activation; and viii) caspase-3 activation. When DNA damage is severe enough that double-strand breaks cannot be repaired via non-homologous end joining (NHEJ), cells rapidly enter apoptosis. Some cells can reach G ₂ phase, but the cells are too damaged to enter M phase and then stop (mediated by cdc2 / cyclin B) and then Eventually apoptosis occurs. Without being limited by a particular theory, because SNS-595 is S phase selective, the dose of SNS-595, a cytotoxic agent for proliferating cells (and thus progressing through the cell cycle including S phase), is Not fatal for non-proliferating cells.

(6.2.1 Solid tumor)
Accordingly, a method of treating, managing or preventing cancer, comprising administering a dose of about 1 mg / m ² to about 100 mg / m ² of SNS-595 in need of such treatment, management or prevention. Provided herein is a method comprising administering to an animal. Cancer types include bladder cancer, breast cancer, cervical cancer, colorectal cancer (including colorectal cancer), esophageal cancer, head and neck cancer, liver cancer, lung cancer (small and non-small cells), melanoma, bone marrow, Including, but not limited to, 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 colon, pancreas, breast, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, melanoma, nasopharynx, neuroendocrine, ovary, kidney, salivary gland, small cell lung cancer or spindle It includes treating, preventing or managing somatic cell cancer.

(6.2.2 Leukemia)
In one embodiment, the methods provided herein are in various forms such as chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukemia and acute myeloblastic leukemia. Treatment, prevention or management of leukemia.

  In some embodiments, the method comprises undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]). , Including myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), megakaryoblastic leukemia (M7), but limited It includes treating, preventing, or managing acute leukemia such as AML. In some embodiments, acute lymphocytic leukemia (ALL) includes leukemias derived from bone marrow (B cells), thymus (T cells) and lymph node blasts. Acute lymphocytic leukemia, according to the French-US-UK (FAB) morphological classification scheme, is L1-matured lymphoblasts (T cells or pre-B cells), L2- immature and polymorphic (various Shape) Classified as lymphoblasts (T cells or pre-B cells) and L3-lymphoblasts (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 myeloid leukemia is myelomonocytic leukemia (M4 or M4 variant with eosinophilia [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 megakaryoblastic leukemia (M7).
In one embodiment, the acute lymphocytic leukemia is derived from bone marrow (B cell) blasts.
In one embodiment, the acute lymphocytic leukemia is derived from the thymus (T cell).
In one embodiment, the acute lymphocytic leukemia is from a lymph node.

In one embodiment, the acute lymphoblastic leukemia is type L1 characterized by mature appearance lymphoblasts (T cells or pre-B cells).
In one embodiment, the acute lymphoblastic leukemia is type L2 characterized by immature and polymorphic (various shapes) lymphoblasts (T cells or pre-B cells).
In one embodiment, the acute lymphocytic leukemia is type L3 characterized by lymphoblasts (B cells; Burkitt cells).

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

  In some embodiments, SNS-595 is used to treat drug resistant leukemias such as chronic myelogenous leukemia (CML). Thus, treatment with SNS-595 can provide an option for patients who do not respond to other treatment methods. In some embodiments, such other methods of treatment include treatment with Gleevec®. In some embodiments, provided herein are methods of treating Philadelphia chromosome positive chronic myelogenous leukemia (Ph + CML). In some embodiments, provided herein are methods of treating Gleevec® resistant Philadelphia chromosome positive chronic myeloid leukemia (Ph + CML).

  The methods provided herein include treating patients who have been previously treated for cancer but are unresponsive to standard therapies, as well as those who have not been previously treated. Also encompassed are methods of treating a patient regardless of the patient's age, although some diseases or disorders are more common in certain age groups. Further provided are methods of treating patients who have undergone surgery in an attempt to treat the disease or condition in question, as well as those who have not. Because patients with cancer have heterogeneous clinical symptoms and various clinical outcomes, the treatment given to the patient may vary depending on his / her prognosis. Skilled clinicians use standard non-drug-based drugs that can be used efficiently to treat individual patients with specific secondary drugs, types of surgery and cancer without undue experimentation The type of treatment can be easily determined.

  The dose of SNS-595 administered can be as a single dose, such as an IV push (e.g., a single bolus) for a period of 10-15 minutes, or over a period of time, e.g., a period of 24 hours (e.g., Can be delivered over a period of time (continuous infusion or divided over a period of time) and, for example, until the patient experiences stable disease or regression, or the patient progresses disease or unacceptable toxicity Repeat until you experience. For example, stable disease for solid tumors generally means that the measurable vertical diameter of the lesion has not increased by more than 25% since the last measurement. For example, Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92 (3): 205-216 (2000) Please refer to. Stable disease or lack thereof is relevant in the art, such as patient symptom assessment, physical examination, visualization of tumors imaged using X-ray, CAT, PET or MRI scans and other commonly accepted assessment modalities Determined by known methods.

In another embodiment, the amount is about ^{10mg / m 2 ~100mg / m 2} . In another embodiment the dose is about ^{30mg / m 2 ~75mg / m 2} . In another embodiment the dose is about ^{40mg / m 2 ~80mg / m 2} . In another embodiment the dose is about ^{50mg / m 2 ~90mg / m 2} .
In another embodiment the dose is about ^{15mg / m 2 ~80mg / m 2} .

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

In other embodiments, SNS-595 is administered in combination with another drug (“second active agent”) or another therapy to treat, manage, or prevent cancer. Second active agents include small and large molecules (eg, proteins and antibodies), examples of which are provided herein, and stem cells or cord blood. Methods or therapies that can be used in combination with the administration of SNS-595 include surgery, immunotherapy, biological therapy, radiation therapy and currently used to treat, prevent or manage cancer. Including, but not limited to, other non-drug based therapies. Various dosing schedules for administration of SNS-595 alone and / or in combination therapy are discussed herein.
Also provided are pharmaceutical compositions (eg, single unit dosage forms) that can be used in the methods disclosed herein. Certain pharmaceutical compositions include SNS-595 and a second active agent.

(6.3 Dose and dosing schedule)
In one embodiment, a method of treating cancer provided herein, prevent, or manage, with respect to the patient, on the basis of body surface area, about 1mg / m ² ~150mg / m ² Including administering a dose of SNS-595. In another embodiment, the method comprises administering a SNS-595 dose of about ^{1mg / m 2 ~100mg / m 2} . In another embodiment, the method comprises administering a SNS-595 dose of about ^{1mg / m 2 ~75mg / m 2} . In another embodiment, the method comprises administering a SNS-595 dose of about ^{1mg / m 2 ~60mg / m 2} . In another embodiment, the method comprises administering a SNS-595 dose of about ^{1mg / m 2 ~50mg / m 2} . In another embodiment, the method comprises administering a SNS-595 dose of about ^{1mg / m 2 ~48mg / m 2} . In another embodiment, the method comprises administering a SNS-595 dose of about ^{1mg / m 2 ~24mg / m 2} . In another embodiment, the method is based on body surface area, which comprises administering an SNS-595 dose of about ^{3mg / m 2 ~27mg / m 2} . In another embodiment, the method comprises administering about 3mg / m ² SNS-595 dose of 24 mg / m ² of ~ based on body surface area. In another embodiment, the method comprises administering a SNS-595 dose of about 10mg / m ² ~90mg / m ² on the basis of body surface area. In another embodiment, comprising administering about 15 mg / m ² doses of SNS-595 in to 80 mg / m ² on the basis of body surface area of the process. In another embodiment, the body surface area calculation can be calculated, for example, with the Mosteller equation:
The square root of BSA (m ² ) = [(height (cm) × weight (kg) / 3600].

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

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

In another embodiment, the dose is 15mg / m ² ~80mg / m ² on the basis of body surface area. In another embodiment, the dose is 15mg / m ² ~75mg / m ² on the basis of body surface area. In another embodiment, the dose is ^{20mg / m 2 ~65mg / m 2} . In another embodiment, the dose is ^{30mg / m 2 ~50mg / 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 , based on body surface area. 50 mg / m ² , 55 mg / m ² , 60 mg / m ² , 65 mg / m ² , 70 mg / m ² , 75 mg / m ² or 80 mg / m ² .

Dose of SNS-595 to be administered may be expressed in units other than as mg / m ^2. For example, the dose can be expressed as mg / kg. One skilled in the art will readily know how to convert doses from mg / m ² to mg / kg for either height or weight of the subject, or both (http: // www. (See fda.gov/cder/cancer/animalfrarne.htrn). For example, a dose of 1mg / m ² ~30mg / m ² for human 65kg is approximately equal to 0.026mg / kg~0.79mg / kg. In another example, a dose of 3 mg / m ² for a 65 kg human is approximately equal to 0.078 mg / kg. In another example, a dose of 15mg / m ² ~80mg / m ² for human 65kg is approximately equal to 0.39mg / kg~2.11mg / kg.

  In certain embodiments, the dose of SNS-595 administered is a single dose, such as an IV push (e.g., a single large bolus IV injection) for a period of 10-15 minutes, or such as a period of 24 hours, etc. Can be delivered over a period of time (e.g., continuous infusion over a period of time or divided bolus administration over a period of time), as needed, e.g., until the patient experiences stable disease or regression, or the patient Repeat until you experience disease progression or unacceptable toxicity. Stable disease or lack thereof is determined by methods known in the art, such as assessment of patient symptoms, physical examination and other commonly accepted assessment modalities.

The amount of pharmaceutical composition administered according to the methods provided herein will depend on the mammal being treated, the severity of the disorder or the symptom of the disorder, the mode of administration, the frequency of administration and the judgment of the prescribing physician. Let's go.
In some embodiments, the frequency of administration ranges from about once a day to about once a month. In certain embodiments, administration is once a day, once every other day, twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks Once every time. In one embodiment, the pharmaceutical compositions provided herein are administered weekly.

  In certain embodiments, SNS-595 is administered to the patient periodically. Cycling therapy involves the administration of an active agent for a while followed by a pause for a while, and this continuous administration is repeated. Cycling therapy can reduce the development of resistance to one or more therapies, avoid or reduce one side effect of the therapy, and / or improve the effectiveness of the treatment.

  Consequently, in one embodiment, SNS-595 is administered weekly in single or divided doses of a 3-6 week cycle with a rest period of about 1 to about 30 days. In another embodiment, SNS-595 is in a resting day of 1, 3, 5, 7, 9, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29 or 30 days, 1 week Administered weekly in single or divided doses for 2, 3, 4, 5 or 6 weeks. 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 there is sufficient bone marrow recovery. The frequency, number and length of dosing cycles can be increased or decreased. Thus, another embodiment includes administration of SNS-595 for more cycles than is typical when it is administered alone.

In one embodiment, the methods provided herein is: i) administering a SNS-595 dose of about 1mg / m ² ~150mg / m ² relative to the patient; ii) any way to a mammal SNS-595 is not administered, it waits for a period of at least 1 day; comprising administering a and iii) a further dose of about 1mg / m ² ~150mg / m ² of SNS-595 to a patient. In one embodiment, steps ii) -iii) are repeated multiple times. In another embodiment, the method comprises administering a dose of 1mg / m ² ~100mg / m ² in step i) and iii).

In one embodiment, for example, in a method for the treatment of certain leukemias, the methods provided herein: i) a 10mg / m ² ~150mg / m ² to mammalian dose SNS- 595 administering a; ii) any SNS-595 to the mammal is not administered, it waits for a period of at least 1 day; iii) further dose of about 10mg / m ² ~150mg / m ² to a mammal Administering SNS-595; and iv) repeating steps ii) to iii) multiple times. In another embodiment, the method comprises administering a dose of 10mg / m ² ~100mg / m ² in step i) and iii).

In one embodiment, the methods provided herein: i) at all that ii) the mammal to be administered the SNS-595 dose of about 1mg / m ² ~75mg / m ² to a patient SNS-595 is not administered, it waits for a period of at least 1 day; comprising administering a and iii) SNS-595 additional dose of about 1mg / m ² ~75mg / m ² to a patient. In one embodiment, steps ii) -iii) are repeated multiple times.

In one embodiment, the methods provided herein include: i) administering a dose of about 1 mg / m ² to about 48 mg / m ² of SNS-595 to a patient; ii) to a mammal is no SNS-595 is not administered, it waits for a period of at least 1 day; comprising administering a and iii) SNS-595 additional dose of about 1mg / m ² ~48mg / m ² to a patient. In one embodiment, steps ii) -iii) are repeated multiple times.

In one embodiment, the methods provided herein: i) administering a SNS-595 dose of about 1mg / m ² ~24mg / m ² relative to the patient; ii) to a mammal no SNS-595 is not administered, it waits for a period of at least 1 day; comprising administering a and iii) SNS-595 additional dose of about 1mg / m ² ~24mg / m ² to a patient. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the method includes the step i) and iii) administering a dose of 3 mg / m ² ~ about 24 mg / m ² in. In yet another embodiment, the method comprises administering a dose of about 15 mg / m ² in steps i) and iii). In yet another embodiment, the method comprises about 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). comprising the administration of ^two or dose of about ^{3mg / m 2 ~24mg / m 2} .

The method in another embodiment comprises administering about 15 mg / m ² doses of to 80 mg / m ² in step i) and iii). In yet another embodiment, the method comprises administering about 15 mg / m ² doses of to 75 mg / m ² in step i) and iii). In yet another embodiment, the method is about 20mg / m ² ~65mg / m ² in step i) and iii), of about ^{30mg / m 2 ~50mg / m 2} , about 35mg / m ² ~40mg / m ² Or administering a dose of about 45 mg / m ² .

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

  In another embodiment, the dosing method comprises administering a dose of SNS-595 to a mammal twice a week (dosing on days 1, 4, 8, and 11). In another embodiment, the dosing method comprises administering a weekly dose of SNS-595 to the mammal. In another embodiment, the dosing method comprises administering a dose of SNS-595 to the mammal every two weeks. In another embodiment, the dosing method comprises administering a dose of SNS-595 to the mammal every 3 weeks. In another embodiment, the dosing method comprises administering a dose of SNS-595 to the mammal every 4 weeks.

  In another embodiment, the dosing method comprises a cycle, wherein the cycle is administered SNS-595 to the mammal once a week for 3 weeks, followed by at least 14 days of SNS-595. And the cycle is repeated multiple times. In another embodiment, the period during which SNS-595 is not administered is 14 days. In another embodiment, the period during which SNS-595 is not administered is 21 days.

In another embodiment, the methods provided herein: i) between 3 weeks to the mammal, the SNS-595 once about 1mg / m ² ~100mg / m ² doses per week Ii) No SNS-595 administered to the mammal, wait for a period of 14 days; and iii) About 1 mg / m ^{2 to} 100 mg once a week for 3 weeks to the mammal administration of an additional dose of SNS-595 at / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein: i) between 3 weeks to the mammal, the SNS-595 once about 1mg / m ² ~75mg / m ² doses per week Ii) No SNS-595 administered to mammals, wait for a period of 14 days; and iii) About 1 mg / m ^{2 to} 75 mg once a week for 3 weeks for mammals administration of an additional dose of SNS-595 at / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein: i) between 3 weeks to the mammal, the SNS-595 once about 1mg / m ² ~60mg / m ² doses per week Ii) No SNS-595 administered to the mammal, wait for a period of 14 days; and iii) About 1 mg / m ^{2 to} 60 mg once a week for 3 weeks to the mammal administration of an additional dose of SNS-595 at / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein: i) between 3 weeks to the mammal, the SNS-595 once about 1mg / m ² ~50mg / m ² doses per week Ii) No SNS-595 administered to the mammal, wait for a period of 14 days; iii) About 1 mg / m ^{2 to} 50 mg / week once a week for 3 weeks for the mammal administering m ² further doses of SNS-595; and iv) repeating steps ii) through iii) multiple times.

In another embodiment, the methods provided herein: i) between 3 weeks to the mammal, the SNS-595 once about 1mg / m ² ~48mg / m ² doses per week Ii) no SNS-595 administered to the mammal, wait for a period of 14 days; and iii) about 1 mg / m ^{2 to} 48 mg once a week for 3 weeks to the mammal administration of an additional dose of SNS-595 at / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein: i) between 3 weeks to the mammal, the SNS-595 once about 1mg / m ² ~24mg / m ² doses per week Ii) No SNS-595 administered to the mammal, wait for a period of 14 days; and iii) About 1 mg / m ^{2 to} 24 mg once a week for 3 weeks to the mammal administration of an additional dose of SNS-595 at / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein: i) between 3 weeks to the mammal, the NS-595 of one to about 2mg / m ² ~40mg / m 2 doses per week Ii) no SNS-595 administered to the mammal, wait for a period of 14 days; and iii) 2 mg / m ^{2 to} 40 mg / week for 3 weeks once a week for the mammal administration of an additional dose of m ² of SNS-595. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein: i) between 3 weeks to the mammal, the NS-595 of one to about 3mg / m ² ~24mg / m ² doses per week Ii) No SNS-595 administered to the mammal, wait for a period of 14 days; and iii) About 3 mg / m ^{2 to} 24 mg once a week for 3 weeks to the mammal administration of an additional dose of SNS-595 at / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include: i) about 3 mg / dose of a mammal once a week (eg, dosed on days 1, 8, and 15) for 3 weeks. administer SNS-595 at a dose of m ^{2 to} 24 mg / m ² ; ii) no SNS-595 is administered to the mammal, wait for a period of at least 28 days; and iii) 3 for mammals during the week, comprising administering once about 3mg / m ² SNS-595 additional dose of ~24mg / m ² weekly. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include: i) a mammal twice a week for 2 weeks (dosed on days 1, 4, 8, and 11) at about 3 mg / Administer SNS-595 at a dose of m ^{2 to} 24 mg / m ² ; ii) No SNS-595 administered to the mammal, wait for a period of at least 28 days; and iii) 2 weeks for the mammal between twice a week (1 day, 4 days, dosing on day 8 and 11 days) comprising administering an SNS-595 additional dose of about ^{3mg / m 2 ~24mg / m 2} . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include: i) about 3 mg / dose of a mammal once a week for 3 weeks (eg, dosing on days 1, 8, and 15). Administer SNS-595 at a dose of m ^{2 to} 24 mg / m ² ; ii) No SNS-595 administered to the mammal, wait for a period of 28 days; and iii) 3 weeks for the mammal between, comprising administering a single additional dose of about 3mg / m ² ~24mg / m ² of SNS-595 per week. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include: i) about 3 mg twice a week (dose on days 1, 4, 8, and 11) for 2 weeks to a mammal administer SNS-595 at a dose of / m ^{2 to} 24 mg / m ² ; ii) no SNS-595 administered to the mammal, wait for a period of 28 days; and iii) 2 for mammals during the week, twice a week (1 day, 4 days, dosing at 8 days and 11 days) comprising administering an SNS-595 additional dose of about ^{3mg / m 2 ~24mg / m 2} . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein: i) between 3 weeks to the mammal, the SNS-595 once about 15mg / m ² ~80mg / m ² doses per week Ii) No SNS-595 administered to mammals, wait for a period of 14 days; and iii) About 15 mg / m ^{2 to} 80 mg once a week for 3 weeks for mammals administration of an additional dose of SNS-595 at / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include: i) about 15 mg / m once a week (eg, dosed on days 1, 8, and 15) for 3 weeks to a mammal administering a ² to 80 mg / m SNS-595 doses of ^2; ii) any SNS-595 is not administered to a mammal, we wait for a period of at least 28 days; and iii) 3 weeks to the mammal between, comprising administering once about 15mg / m ² SNS-595 additional doses to 80 mg / m ² weekly. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include: i) about 2 times a week for 2 weeks (dose on days 1, 4, 8, and 11) for a mammal; administering a 15mg / m ² ~80mg / m ² dose SNS-595 to; ii) is no SNS-595 to a mammal not administered, it waits for a period of at least 28 days; and iii) to a mammal in contrast, comprising between 2 weeks, twice a week (1 day, 4 days, dosing on day 8 and 11 days) the administration of a SNS-595 additional dose of about 15mg / m ² ~80mg / m ² . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include: i) about 15 mg / mg of a mammal once a week (eg, dosed on days 1, 8, and 15) for 3 weeks. Administer SNS-595 at a dose between m ^{2 and} 80 mg / m ² ; ii) No SNS-595 administered to the mammal, wait for a period of 28 days; and iii) 3 weeks for the mammal between, comprising administering once about 15mg / m ² SNS-595 additional doses to 80 mg / m ² weekly. In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods provided herein include: i) about 15 mg twice a week (dose on days 1, 4, 8, and 11) for 2 weeks to a mammal administer SNS-595 at a dose of / m ^{2 to} 80 mg / m ² ; ii) no SNS-595 administered to the mammal, wait for a period of 28 days; and iii) 2 for mammals during the week, twice a week (1 day, 4 days, 8 days and dosing of 11 days) comprising administering an SNS-595 additional dose of about ^{15mg / m 2 ~80mg / m 2} . In one embodiment, steps ii) -iii) are repeated multiple times.

In another embodiment, the methods comprise administering an SNS-595 dose once 1mg / m ² ~100mg / m ² weekly for the patient, the period of one week, the treatment cycle And the treatment cycle is repeated at least 3 times. In another embodiment, the methods comprise administering an SNS-595 dose once 1mg / m ² ~75mg / m ² weekly for the patient, the period of one week, the treatment cycle And the treatment cycle is repeated at least 3 times. In another embodiment, the methods comprise administering an SNS-595 dose once 1mg / m ² ~60mg / m ² weekly for the patient, the period of one week, the treatment cycle And the treatment cycle is repeated at least 3 times. In another embodiment, the methods comprise administering an SNS-595 dose once 1mg / m ² ~48mg / m ² weekly for the patient, the period of one week, the treatment cycle And the treatment cycle is repeated at least 3 times. In another embodiment, the methods comprise administering an SNS-595 dose once 1mg / m ² ~24mg / m ² weekly for the patient, the period of one week, the treatment cycle And the treatment cycle is repeated at least 3 times. In another embodiment, the dose is about ^{2mg / m 2 ~40mg / m 2} 1 times a week, the period of one week, comprises a treatment cycle, the treatment cycle is repeated at least three times. In another embodiment, the dose is about ^{3mg / m 2 ~24mg / m 2} 1 times a week, the period of one week, comprises a treatment cycle, the treatment cycle is repeated at least three times. In another embodiment, the dose is about 15 mg / m ² once a week, wherein the one week period includes a treatment cycle and the treatment cycle is repeated at least three times.

In another embodiment, the methods comprise administering an SNS-595 dose once 15mg / m ² ~80mg / m ² weekly for the patient, the period of one week, the treatment cycle And the treatment cycle is repeated at least 3 times. In another embodiment, the methods comprise administering an SNS-595 dose once 15mg / m ² ~75mg / m ² weekly for the patient, the period of one week, the treatment cycle And the treatment cycle is repeated at least 3 times. In another embodiment, the methods comprise administering an SNS-595 dose once 20mg / m ² ~65mg / m ² weekly for the patient, the period of one week, the treatment cycle And the treatment cycle is repeated at least 3 times. In another embodiment, the methods comprise administering an SNS-595 dose once 30mg / m ² ~50mg / m ² weekly for the patient, the period of one week, the treatment cycle And the treatment cycle is repeated at least 3 times.

In some embodiments, the method, once a week to the patient (e.g., 1 day, 8 days and dosing 15 days) of about 1 mg / m ² doses of SNS-595 of 40 mg / m ² The one week period includes a treatment cycle, wherein the treatment cycle is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method, twice a week to a patient (1 day, 4 days, dosing on day 8 and 11 days) of about 1mg / m ² ~40mg / m ² dose SNS- The period of 1 week comprising administering 595 includes a treatment cycle, the treatment cycle is repeated at least 3 times, followed by a waiting period of at least 28 days. In some embodiments, the method, once a week to the patient (e.g., 1 day, 8 days and dosing 15 days) of about 1 mg / m ² doses of SNS-595 of 40 mg / m ² The one week period, including administration, includes a treatment cycle, which is repeated at least three times, followed by a 28 day waiting period. In some embodiments, the method, twice a week to a patient (1 day, 4 days, dosing on day 8 and 11 days) of about 1mg / m ² ~40mg / m ² dose SNS- The one week period that includes administering 595 includes a treatment cycle, which is repeated at least three times, followed by a waiting period of 28 days.

In some embodiments, the method, once a week to the patient (e.g., 1 day, 8 days and dosing 15 days) of about 3 mg / m ² doses of SNS-595 in ~24mg / m ² The one week period includes a treatment cycle, wherein the treatment cycle is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method, twice a week to a patient (1 day, 4 days, dosing on day 8 and 11 days) of from about 3mg / m ² ~24mg / m ² dose SNS- The period of 1 week comprising administering 595 includes a treatment cycle, the treatment cycle is repeated at least 3 times, followed by a waiting period of at least 28 days. In some embodiments, once a week to the patient (e.g., 1 day, 8 days and dosing 15 days) administering about 3 mg / m ² doses of SNS-595 in ~24mg / m ² The one week period includes a treatment cycle, which is repeated at least three times, followed by a waiting period of 28 days. In some embodiments, the method, twice a week to a patient (1 day, 4 days, dosing on day 8 and 11 days) of from about 3mg / m ² ~24mg / m ² dose SNS- The one week period that includes administering 595 includes a treatment cycle, which is repeated at least three times, followed by a waiting period of 28 days.

In some embodiments, the method, once a week to the patient (e.g., 1 day, 8 days and dosing 15 days) of about 15 mg / m ² doses of SNS-595 in to 80 mg / m ² The one week period includes a treatment cycle, wherein the treatment cycle is repeated at least three times, followed by a waiting period of at least 28 days. In some embodiments, the method, twice a week to a patient (1 day, 4 days, dosing on day 8 and 11 days) of from about 15mg / m ² ~80mg / m ² dose SNS- The period of 1 week comprising administering 595 includes a treatment cycle, the treatment cycle is repeated at least 3 times, followed by a waiting period of at least 28 days. In some embodiments, the method, once a week to the patient (e.g., 1 day, 8 days and dosing 15 days) of about 15 mg / m ² doses of SNS-595 in to 80 mg / m ² The one week period, including administration, includes a treatment cycle, which is repeated at least three times, followed by a 28 day waiting period. In some embodiments, the method, twice a week to a patient (1 day, 4 days, dosing on day 8 and 11 days) of from about 15mg / m ² ~80mg / m ² dose SNS- The one week period that includes administering 595 includes a treatment cycle, which is repeated at least three times, followed by a waiting period of 28 days.

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

(6.4 Exemplary medication plan)
Exemplary dosing schedules related to specific cancers are provided below. These dosing schedules are intended to be illustrative but not exclusive.
In one embodiment, a method for treating a solid tumor is provided. This method:
i) administering SNS-595 in a dose of about 1mg / m ² ~100mg / m ² to the patient;
ii) wait at least a 6-day period in which subjects will not receive any SNS-595;
iii) administering SNS-595 in a further dose of about 1mg / m ² ~100mg / m ² to the patient, and,
iv) repeating steps ii) to iii) multiple times,
including.

In another embodiment, the method for treating solid tumors, comprising administering once about ^{1mg / m 2 ~75mg / m SNS} -595 doses of ² per week to the patient for a period of 1 week Includes a treatment cycle, and the treatment cycle is repeated at least twice. In another embodiment the dose is about ^{15mg / m 2 ~80mg / m 2} . In another embodiment the dose is about ^{3mg / m 2 ~24mg / m 2} .

In another embodiment, the method for treating solid tumors, during 3 weeks for the patient, administered once about ^{15mg / m 2 ~40mg / m SNS} -595 doses of ² per week, followed by Including at least a two-week period in which SNS-595 is not administered to the subject, and the cycle is repeated multiple times. In another embodiment the dose is about ^{15mg / m 2 ~35mg / m 2} . In another embodiment the dose is about ^{20mg / m 2 ~30mg / m 2} . In another embodiment the dose is about ^{20mg / m 2 ~25mg / m 2} .

In another embodiment, the method for treating solid tumors, comprising administering an SNS-595 once about 35 mg / m ² doses of to 80 mg / m ² in a period of three weeks to a patient, 3 weeks The period includes a treatment cycle and the treatment cycle is repeated at least twice.
In another aspect, provided herein is a method of treating a hematological malignancy. Such methods are described in particular embodiments, comprising administering an SNS-595 dose of about 20mg / m ² ~60mg / m ² to a patient.

In patients considered many times treated in advance ( "patients treated beforehand times"), the method, once during the 3 weeks to patients 35mg / m ² ~60mg / m ² In a three week period, including a treatment cycle, and the treatment cycle is repeated at least twice. In another embodiment, the method for treating a patient many times treated in advance, comprises administering a dose of ^{40mg / m 2 ~50mg / m 2} . In another embodiment, the method for treating a patient many times treated in advance, comprises administering a dose of ^{45mg / m 2 ~50mg / m 2} . Patients who have been pre-treated many times are defined as described by Toicher et al., J. Gun. Oncol. 19: 2937-2947 (2001) Course, more than 2 carboplatin or mitomycin C courses, any previous nitrosourea containing therapy, irradiation to 25% of bone marrow containing areas, high dose chemotherapy requiring infusion of hematopoietic stem cells or extensive bone Patients who have been previously treated with metastases.

Patients whose previous solid tumors have not been treated or have been treated but are not considered to have been pre-treated many times are minimally pre-treated (`` Minimum pre-treatment Patient "). To treat patients minimally treated beforehand, the method comprises administering once ^{45mg / m 2 ~80mg / m SNS} -595 doses of ² to periods of three weeks to a patient A three week period includes a treatment cycle and the treatment cycle is repeated at least twice. In another embodiment, the method for treating a patient treated in advance to a minimum, comprises administering a dose of ^{50mg / m 2 ~75mg / m 2} . In another embodiment, the method for treating a patient treated in advance to a minimum, comprises administering a dose of ^{55mg / m 2 ~70mg / m 2} . In another embodiment, the method for treating a patient treated in advance to a minimum, comprises administering a dose of ^{55mg / m 2 ~65mg / m 2} .

In another aspect, a method for treating blood cancers such as leukemias and lymphomas is provided. This method:
i) administering a dose of SNS-595 of 10mg / m ² ~50mg / m ² to the patient;
ii) Wait at least a two-day period in which the subject will not receive any SNS-595;
iii) administering the SNS-595 additional doses of 10mg / m ² ~50mg / m ² to the patient; and
iv) repeating steps ii) to iii) multiple times,
including.

In one embodiment, the waiting period is 6 days. In another embodiment, the waiting period is 2 days. In another embodiment, the waiting period is 3 days.
In one embodiment, the method of treating a hematological malignancy comprises about 20 mg / m ² , 22 mg / m ² , 25 mg / m ² , 27 mg / m ² or 30 mg / m ² once a week for the patient. Administering a dose of SNS-595, the one week period includes a treatment cycle, and the treatment cycle is 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 ² of SNS-595 once a week for a period of one week. Cycle, and the treatment cycle is repeated at least twice.

Other dosing schedules useful for treatment of hematologic malignancies patients during 2 weeks, about 25 mg / m ² ~ about 50 mg / m ² 2 times a week can including being administered. In another embodiment, the dosing schedule used in the treatment of hematologic malignancies, including during the two weeks, that about about 30 mg / m ² ~ about 45 mg / m ² 2 times per week is administered. In another embodiment, the dosing schedule for the treatment of hematological malignancy includes administration of 30, 35, 40, or 45 mg / m ² twice a week for 2 weeks.

In one embodiment, the method of treating a hematological malignancy comprises about 40 mg / m ² , 45 mg / m ² , 50 mg / m ² , 55 mg / m ² or 60 mg / m ² once every 2 weeks for a patient. Administration of a dose of SNS-595, and a two week period includes a treatment cycle. In one embodiment, a method of treating a hematological malignancy comprises administering to a patient a dose of about 50 mg / m ² of SNS-595 once every two weeks, and during the two week period, Includes cycle.

(6.5 Combination therapy)
In the methods and compositions provided herein, SNS-595 can be used with or combined with other pharmacologically active compounds (“second active agents”). Certain combinations are believed to work synergistically in the treatment of certain types of cancer. SNS-595 can also act to reduce the adverse effects associated with certain second active agents, and some second active agents reduce the adverse effects associated with SNS-595 Can be used for.

(6.5.1 Second active agent)
One or more second active ingredients or agents can be used with SNS-595 in the methods and compositions provided herein. The second active agent can be a large molecule (eg, a protein) or a small molecule (eg, a synthetic inorganic molecule, an organometallic molecule, or an organic molecule).

  Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines and monoclonal and polyclonal antibodies, particularly therapeutic antibodies against cancer antigens. Typical large molecule active agents are biomolecules such as naturally occurring or artificially produced proteins. Proteins and compositions that are particularly useful for the methods provided herein include proteins that stimulate the survival and / or proliferation of hematopoietic progenitor cells and immunologically active poietic cells in vitro or in vivo. including. Others stimulate the division and differentiation of committed erythroid precursors in cells in vitro or in vivo. Specific proteins include: IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), interleukins such as IL-10, IL-12 and IL-18; interferon alpha-2a , Interferons such as, interferon α-2b, interferon α-n1, interferon α-n3, interferon β-I, and interferon γ-Ib; GM-CF and GM-CSF; and EPO.

  Specific proteins that can be used in the present methods and compositions include: filgrastim (Amgen, Thousand Oaks, CA) and pegfillgrass sold in the United States under the trade name Neupogen® Derivatives thereof including but not limited to pegfilgrastim; Immunex, Seattle, WA sold in the United States under the trade name Leukine®; trade name Epogen® Recombinant EPO (Amgen, Thousand Oaks, CA) sold below in the United States; epoetin alfa; and darbepoetin alfa, without limitation.

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

  Also provided are natural, naturally occurring, and recombinant proteins for use in combination with SNS-595. Also included are mutants and derivatives (eg, modified forms) of naturally occurring proteins that exhibit at least some of the pharmacological activity of the protein on which they are based in vivo. Examples of mutants include, but are not limited to, proteins having one or more amino acid residues that differ from the corresponding residues in the naturally occurring form of the protein. Also encompassed by the term “mutant” are proteins that lack a hydrocarbon moiety, usually present in these naturally occurring forms (eg, non-glycosylated forms). Examples of derivatives include, but are not limited to, fusion proteins such as PEGylated derivatives and proteins or proteins formed by fusing IgG1 or IgG3 to the active portion of the protein of interest. See, for example, 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 trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (Avastin®), pertuzumab (Omnitarg®) ), Tositumomab (Bexxar®), edrecolomab (Panorex®) and G250. SNS-595 can also be used in combination with or in combination with an anti-TNF-α antibody and / or an anti-EGFR antibody such as Erbitux (registered trademark) or panitumumab.

  Large molecule active agents may be administered in the form of anti-cancer vaccines. For example, vaccines that secrete or cause secretion of cytokines such as IL-2, G-CSF and GM-CSF can be used in the provided methods and pharmaceutical compositions. See, for example, Emens, LA A. et al., Curr. Opinion Mol. Ther. 3 (1): 77-84 (2001).

  In contrast to the general rule that drugs with different mechanisms of action are selected to maximize the potential for additive or synergistic effects (e.g., Page, R. and Takimoto, C., `` Combinations involving the Principles of Chemotherapy, Cancer Management: A Multidisciplinary Approach (2001), p. 23), SNS-595 and also a second agent that interferes with DNA synthesis are additive. Have been found to be synergistic or synergistic.

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

  Since SNS-595 affects the DNA-PK pathway, the second agent may be an agent that mediates its cytotoxicity via the DNA-PK pathway. One example is an agent that inhibits non-homologous endjoining repair, such as a DNA-PK inhibitor. As used herein and unless otherwise specified, the term “DNA-PK inhibitor” means an agent that inhibits or interferes with a signaling pathway mediated by DNA-PK. Inhibition of DNA-PK activity may be direct (e.g., a catalytic inhibitor of DNA-PK itself) or indirect (e.g., active DNA-PK complexes (DNA-PK, Ku70 and Drugs that prevent the formation of Ku80). Other examples include, but are not limited to, ligase IV inhibitors and apoptosis enhancers such as caspase-9 activators, caspase-3 activators and Hsp90 inhibitors.

In addition, a second active agent that is a small molecule can be used to reduce the adverse effects associated with administration of SNS-595. However, like some large molecules, it is believed that many can produce a synergistic effect when administered with SNS-595 (eg, before, after, or simultaneously). Examples of small molecule second active agents include, but are not limited to, anticancer agents, antibiotics, immunosuppressive factors and steroids.
Examples of anticancer agents include alkylating agents, antineoplastic agents, antimetabolites (e.g., folic acid analogs, purine analogs, adenosine analogs, pyrimidine analogs and substituted ureas), platinum coordination compounds, topoisomerase II Including but not limited to inhibitors and radiation.

  Specific anti-cancer drugs include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronin; adzelesin; aldesleukin; altretamine; ambomycin; amethanetron acetate; amsacrine; Asparaginase; asperlin; azacitidine; azetepa; azetepa; azotomycin; battomycin; benzodepa; bicalutamide; bicalutamide hydrochloride; Capecitabine; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; Celecoxib (COX-2 inhibitor); chlorambucil; cilolemycin; cisplatin; cladribine; krisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; Dizacone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drmostanolone propionate; duazomycin; edatrexate; Epipropidine; epirubicin hydrochloride; erbulozole; erlotinib; esorubicin hydrochloride; estramustine; estram phosphate Sutin sodium; etanidazole; etoposide; etoposide phosphate; etoprine; etoprine; fadrozol hydrochloride; fazarabine; fenretinide; floxuridine; Urea; idarubicin hydrochloride; ifosfamide; ilmophosin; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; riarosol hydrochloride hydrochloride; Melengestrol acetate; Melphalan; Menogalyl; Mercaptopri Methotrexate; methotrexate sodium; methoprin; metredepa; mitindamide; mitocarcin; mitocromin; mitodiline; mitomalcin; mitomycin; mitosper; Olumaplatin; oxythran; paclitaxel; pegaspargase; peliomycin; peliomycin; pemetrexed; Prednimastine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; Ribopurine; saphingol; saphingol hydrochloride; semustine; simtrazen; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; slofenur; thalomycin, tecogalan sodium; Telofurone; teloxantrone hydrochloride; temoporfin; teniposide; teloxilone; test lactone; thiamiprine; thioguanidine; thioguanine; thiotepa; Trimethrexate glucuronate; Triptorelin; Tubrosol hydrochloride; Uracil mustard; Uredepa; Vapreotide; Tepolfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinipezine sulfate; vinglycurate sulfate; vinleurosine sulfate; vinoleurosine tartrate; And zorubicin hydrochloride.

Other anticancer agents include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipepenol; adzelesin; aldesleukin; Amtrexin; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antalix; antidorpomorphic morphogenic protein; -1; anti-androgen, prostate cancer; anti-estrogen; antineoplastic drug; antisense oligonucleotide; aphidicolin glycinate; apoptosis gene modulator; apoptosis regulator; -DL-PTBA; arginine deaminase; aslacrine; atamestan; attritin; axinastatin 1; axinastatin 1; axinastatin 3; azasetron; azatoxin; azatyrosine; bacimastat; BCR / ABL antagonist; benzochlorin; benzoyl staurosporine; β-lactam derivative; β-alethine; betaclamicin B; betulinic acid; bFGF inhibitor; bicalutamide; Lysinyl spermine; bisnafide; bistratene A; biselecine; breflate; bropyrimine; bud titanium; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivative; Carolinamide triazole; CaRest M3; CARN 700; cartilage-derived inhibitor; calzeresin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; Porphyrin; cladribine; clomiphene analog; clotrimazole; collismycin A; chorismycin B; combretastatin A4; combretastatin analog; conagenin; crambescidin 816; crisnatol; Ficin A derivative; curacin A; cyclopentanthraquinone; cycloplatam; cypemycin; cytarabine ocphosphate; cytolytic factor; cytostatin; daclixima (dacliximab); decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexifosfamide; dexrazoxane; dexverapamil; diazicon; didemnin B; Azacitidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxyfluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; Elemene; Emiteflu; Epirubicin; Epristeride; Estramustine analog; Estrogen agonist; Estrogen antagonist; Etanidazo Etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; frazepilin; fluasterone; fluasterabine; fluorodaunorunicin hydrochloride; Texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitor; gemcitabine; glutathione inhibitor; hepsulfam; helegin; hexamethylenebisacetamide; For example, Gleevec®); imiquimod; immunostimulatory peptide; insulin-like Growth factor-1 receptor inhibitor; interferon agonist; interferon; interleukin; iobenguan; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron Jaspraquinolide; kahalalide F; lamellarin-N triacetate; lanreotide; reinamycin; lenograstim; lentinan sulfate; leptolstatin; leptolstatin; letrozole; leukemia inhibitor; Leuprorelin; levamisole; riarosol; linear polyamine analogs; lipophilic diglycopeptides; lipophilic platinum compounds; lissoclinamide 7; Lombrexol; Lonidamine; Losoxanthrone; Loxoribine; Lurtotecan; Lutetium texaphyrin; Lysofylline; Lysofylline; Lysofylline; Melbarone; methbarin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitguazone; mitactol; mitomycin analog; methonafide; Morgramostim; erbitux, human chorionic gonadotropin; monophosphoryl lipid A + myobacterium fine Wall sk; mopidamol; mustard anticancer drug; mycaperoxide B; actinomycete cell wall extract; myriaporone; N-acetyldinarine; N-substituted benzamide; nafarelin; nagrestip; + Nazovin; nartograstim; nedaplatin; nemorubicin; neriduronic acid; nilutamide; nisamycin; nitric oxide modulator; nitric oxide antioxidant; nitrullyn; Genasense®; 0 ⁶ -Benzylguanine; Octreotide; Oxenone; Oligonucleotide; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokine inducer; Ormaplatin; Osaralon; Oxa Platin; oxaunomycin; paclitaxel; paclitaxel analogue; paclitaxel derivative; parauamine; palmitoyl lysoxine; pamidronic acid; panaxriol; panomiphene; parabactin; pazelliptin; Pentostatin; pentrozole; perflubron; perphosphamide; perillyl alcohol; phenazinomycin; phenyl acetate; phosphatase inhibitor; picibanil; pilocarpine hydrochloride; pirarubicin; pyritroxime; placetin A; Activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porfimer sodium; porphyromycin; prednisone; Propilagrin J2; Proteasome inhibitor; Protein A-based immunomodulating component; Protein kinase C inhibitor; Protein kinase C inhibitor, microalgae; Protein tyrosine phosphatase inhibitor; Purine nucleoside phosphorylase inhibitor inhibitor Purpurine; Pyrazoloacridine; Pyridoxyl-oxidized hemoglobin polyoxyethylene conjugate; raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; Etidronic acid; lysoxine; ribozyme; RII retinamide; rohitukine; romultide; rokinimex; rubiginone B1; ruboxil; ntopin); SarCNU; sarcophytol A; salgramostim; Sdi1 mimicry; semstin; senescence-derived inhibitor 1; sense oligonucleotide; signaling inhibitor; schizophyllan; sobuzoxane; sodium borocaptate; Somatomedin-binding protein; sonermine; sparfolic acid; spicamycin D; spiromustine; splenopentin; spongatin 1; squalamine; stipiamide; stromelysin inhibitor; sulfinosine; Suramin; swainsonine; talimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; Temoporfin; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Taliblastine; Thiocollaline; Thrombopoietin; Mimic thrombopoietin; Timalfacin; Thymopoietin receptor agonist; Titanocene dichloride; topsentin; toremifene; translation inhibitor; tretinoin; triacetyluridine; triciribine; trimethrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor; Sinus-derived growth inhibitory factor; urokinase receptor antagonist; bapleutide; variolin B; veralesol; veramine; verde Nsu (verdins); verteporfin; vinorelbine; Binkisaruchin; Bitakushin; vorozole; Zanoteron (zanoterone); Zenipurachin; Jirasukorubu; and zinostatin Lamar.

  Specific second active agents include, but are not limited to: rituximab, oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron) (Registered trademark)), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodal, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa (registered trademark), taxol, taxotere, fluorouracil, leucoboline, leucovorin Irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEGINTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal dow Norubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine , Doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac and etoposide.

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

In other embodiments, the second active agent is an adjunct therapeutic agent. An example of an adjuvant treatment is an antiemetic. Specific antiemetics include, but are not limited to, phenothiazine, butyrophenone, benzodiazepine, corticosteroids, serotonin antagonists, cannabinoids and NK ₁ receptor antagonists. Examples of phenothiazine antiemetics include, but are not limited to, prochlorperazine and trimethobenzamide. Examples of butiophenone 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 NK ₁ receptor antagonists include, but are not limited to, aprepitant. The dose and dosing schedule of the antiemetic should depend on the specific indicators being treated, the age and condition of the patient, and the severity of the adverse effects and can thus be adjusted by one skilled in the art. Examples of doses and dosing schedules can be found, for example, in the Physician's Desk Reference.

(6.5.2 Exemplary methods of combination therapy)
In certain embodiments, the methods provided herein comprise administering SNS-595 in combination with one or more second active agents and / or in combination with radiation therapy or surgery. . Administration of SNS-595 and the second active agent to the patient can be performed simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration used for a particular active agent is treated and the active agent itself (eg, whether it can be administered orally without degradation before entering the bloodstream) Depends on the disease. Recommended routes of administration for the second active agent are known to those of skill in the art. For example, see the desktop reference book for doctors (60th edition, 2006).

  In one embodiment, the second active agent is 1 to about 1,000 mg, about 5 to about 500 mg, about 10 to about 375 mg or about intravenously or subcutaneously and in amounts once or twice daily. It is administered in an amount of 50 to about 200 mg. In one embodiment, the second active agent is rituximab, oblimersen (Genasense®), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, Pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine or combinations thereof. In certain embodiments, the second active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, wortmannin, geldanamycin, gemcitabine or theirs It is a combination.

  In another embodiment, a method of treating, preventing and / or managing a hematological malignancy comprising treating, preventing or managing surgery, immunotherapy, biological therapy, radiation therapy or cancer. A method comprising administering SNS-595 (e.g., before, during, or after) in combination with conventional therapy, including but not limited to other non-drug-based therapies currently used to Provided herein. Without being limited by theory, it is believed that SNS-595 can provide an additive or synergistic effect when given concurrently with conventional therapy.

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

In one embodiments, SNS-595 is from about 1 to about 75 mg / m ^2, from 1 to about 600 mg / m ^2, from 1 to about 48 mg / m ^2, from 1 to about 24 mg / m ^2, from 1 to about 50 mg / m ² , about 1 to about 40 mg / m ² , about 1 to about mg / m ² , about 3 to about 30 mg / m ² , about 3 to about 24 mg / m ² , alone or as disclosed herein. It can be administered in combination with the two active agents before, during or after use of conventional therapies.
In another embodiment, the methods provided herein of: a) administering about ^{1mg / m 2 ~75mg / m SNS} -595 doses of ² to a patient in need thereof, and b ) Comprising administering a therapeutically effective amount of an adjuvant therapeutic.

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

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

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

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

In another embodiment, the second agent is an antineoplastic antibiotic and the cancer being treated is bladder cancer, breast cancer, cervical cancer, head and neck cancer, Hodgkin's disease, leukemia, multiple myeloma, nerve Blastoma, 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 / m ² . In another embodiment, the antibiotic is bleomycin and the therapeutically effective amount is between about 10 units / m < ² > and about 20 units / m < ² > intravenous, subcutaneous or intramuscular dose weekly or twice weekly. It is. In another embodiment, the antibiotic is dactinomycin. In another embodiment, the antibiotic is dactinomycin and the therapeutically effective amount is at least 0.01 mg / kg. In another embodiment, the antibiotic is dactinomycin and the therapeutically effective amount is daily intravenous administration between about 0.010 mg / kg to about 0.015 mg / kg for 5 days every 3 weeks. In another embodiment, the antibiotic is dactinomycin and the therapeutically effective amount is an intravenous dose of ² mg / m ² every 3 or 4 weeks. In another embodiment, the antibiotic is daunorubicin. In another embodiment, the antibiotic is daunorubicin and the therapeutically effective amount is at least 30 mg / m ^2. In another embodiment, the antibiotic is daunorubicin and the therapeutically effective amount is an daily intravenous dose of between about 30 mg / m ² ~ about 45 mg / m ² 3 days. In another embodiment, the antibiotic is a liposomal formulation of daunorubicin and the therapeutically effective amount is an intravenous dose of 40 mg / m ² every 2 weeks. In another embodiment, the antibiotic is doxorubicin. In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is at least 15 mg / m ² . In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is intravenous administration between about 60 mg / m < ² > and about 90 mg / m < ² > every 3 weeks. In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is weekly intravenous administration between about 15 mg / m < ² > and about 20 mg / m < ² >. In another embodiment, the antibiotic is doxorubicin and the therapeutically effective amount is a cycle comprising weekly intravenous administration of 30 mg / m ² for 2 weeks followed by no doxorubicin for 2 weeks. .

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

  In another embodiment, the antimetabolite is a purine analog and the cancer being treated is colorectal cancer, leukemia or myeloma. In another embodiment, the purine analog is mercaptopurine. In another embodiment, the purine analog is mercaptopurine and the therapeutically effective amount is at least 1.5 mg / kg. In another embodiment, the purine analog is mercaptopurine and the therapeutically effective amount is a daily oral dose between about 1.5 mg / kg and about 5 mg / kg. In another embodiment, the purine analog is thioguanidine. In another embodiment, the purine analog is thioguanidine and the therapeutically effective amount is at least 2 mg / kg. In another embodiment, the purine analog is thioguanidine and the therapeutically effective amount is a daily oral dose between about 2 mg / kg and about 3 mg / kg.

In another embodiment, the antimetabolite is an adenosine analog and the cancer being treated is leukemia or lymphoma. In another embodiment, the adenosine analog is cladribine. In another embodiment, the adenosine analog is cladribine and the therapeutically effective amount is at least 0.09 mg / kg. In another embodiment, the adenosine analog is cladribine and the therapeutically effective amount is daily intravenous administration of 0.09 mg / kg over 7 days. In another embodiment, the adenosine analog is cladribine and the therapeutically effective amount is daily intravenous administration of 4 mg / m ^{2 over} 7 days. In another embodiment, the adenosine analog is pentostatin. In another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is 4 mg / m ² . In another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is an intravenous dose of 4 mg / m ² every other week. In another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is an intravenous administration of 4 mg / m ² every 3 weeks.

In another embodiment, the antimetabolite is a pyrimidine analog and the cancer being treated is bladder cancer, breast cancer, colorectal cancer, esophageal cancer, head and neck cancer, leukemia, liver cancer, lymphoma, ovarian cancer, pancreatic cancer. Skin cancer or stomach cancer. In another embodiment, the pyrimidine analog is cytarabine. In another embodiment, the pyrimidine analog is cytarabine and the therapeutically effective amount is at least 100 mg / m ² . In another embodiment, the pyrimidine analog is cytarabine and the therapeutically effective amount is a daily intravenous dose of 100 mg / m ^{2 over} 7 days. In another embodiment, the pyrimidine analog is capecitabine. In another embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is a daily amount of at least 2000 mg / m ^2. In another embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is a twice oral daily dose of between about 1200 mg / m ² ~ about 1300 mg / m ² during 14 days . In another embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is about 1250 mg / m ² administered twice daily for 14 days, followed by 3 weeks of rest for 1 week. Cycle. In another embodiment, the pyrimidine analog is fluorouracil. In another embodiment, the pyrimidine analog is fluorouracil and the therapeutically effective amount is at least 10 mg / kg. In another example, the pyrimidine analog is fluorouracil and the therapeutically effective amount is daily intravenous administration between about 300 mg / m ² to about 500 mg / m ² for at least 3 days. In another example, the pyrimidine analog is fluorouracil and the therapeutically effective amount is daily intravenous administration of 12 mg / kg during 3-5 days. In another embodiment, the pyrimidine analog is fluorouracil and the therapeutically effective amount is weekly intravenous administration between about 10 mg / kg to about 15 mg / kg.

  In another embodiment, the antimetabolite is a substituted urea and the cancer being treated is head and neck cancer, leukemia, melanoma or ovarian cancer. In another embodiment, the substituted urea is hydroxyurea. In another embodiment, the substituted urea is hydroxyurea and the therapeutically effective amount is at least 20 mg / kg. In another embodiment, the substituted urea is hydroxyurea and the therapeutically effective amount is an oral dose of 80 mg / kg every 3 days. In another embodiment, the substituted urea is hydroxyurea and the therapeutically effective amount is a daily oral dose between about 20 mg / kg and about 30 mg / kg.

In another embodiment, the second agent is a platinum coordination compound and the cancer being treated is bladder cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, leukemia, lung cancer, lymphoma, ovarian cancer, Sarcoma, testicular cancer or uterine cancer. In another embodiment, the platinum coordination compound is carboplatin. In another embodiment, the platinum coordination compound is carboplatin and the therapeutically effective amount is at least 300 mg / m ² . In another embodiment, the platinum coordination compound is carboplatin and the therapeutically effective amount is at least 300 mg / m ² every 4 weeks. In another embodiment, the platinum coordination compound is carboplatin and the therapeutically effective amount is 300 mg / m ² every 4 weeks. In another embodiment, the platinum coordination compound is carboplatin and the therapeutically effective amount is at least 360 mg / m ² every 4 weeks. In another embodiment, the platinum coordination compound is cisplatin. In another embodiment, the platinum coordination compound is cisplatin and the therapeutically effective amount is at least 20 mg / m ² . In another embodiment, the platinum coordination compound is cisplatin and the therapeutically effective amount is a daily intravenous dose of 20 mg / m ² every 4-4 days every 3-4 weeks. In another embodiment, the platinum coordination compound is cisplatin and the therapeutically effective amount is an intravenous administration of 50 mg / m ² every 3 weeks. In another embodiment, the platinum coordination compound is oxaliplatin. In another embodiment, the platinum coordination compound is oxaliplatin and the therapeutically effective amount is at least 75 mg / m ² . In another embodiment, the platinum coordination compound is oxaliplatin and the therapeutically effective amount is between about 50 mg / m ² and about 100 mg / m ² . In another embodiment, the platinum coordination compound is oxaliplatin and the therapeutically effective amount is an IV infusion of between about 50 mg / m ² ~ about 100 mg / m ² every two weeks. In another embodiment, the platinum coordination compound is oxaliplatin and the therapeutically effective amount is an IV infusion of between about 80 mg / m ² ~ about 90 mg / m ² every two weeks. In another embodiment, the platinum coordination compound is oxaliplatin and the therapeutically effective amount is a 2-hour IV infusion of 85 mg / m ² 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 / m ² . In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is between 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 3 or 4 weeks, at least 3 times during 5 days each, about 35 mg / m ² per day to about 50 mg / m ² Intravenous administration. 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 per day, at least three times every five days every three or four weeks. Intravenous administration between ² . In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is an oral dose of 100 mg / m ² per day at least three times during 5 days every 3 or 4 weeks. In another embodiment, the topoisomerase II inhibitor is teniposide. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is at least 20 mg / m ² . In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is a dose of 100 mg / m ² weekly. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is a dose of 100 mg / m ² twice weekly. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is a dosage of between about 20 mg / m ² ~ about 60 mg / m ² daily for 5 days. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is a dosage of between about 80 mg / m ² ~ about 90 mg / m ² daily for 5 days.

(6.6 Pharmaceutical compositions and dosage forms)
The methods provided herein use a pharmaceutical composition comprising SNS-595 and a pharmaceutically acceptable carrier such as a diluent or adjuvant, or in combination with other active ingredients such as another anticancer agent. In clinical practice, SNS-595 can be administered by any conventional route including, but not limited to, orally, parenterally, rectally, or by inhalation (e.g., in the form of an aerosol). Good. In some embodiments, the compositions provided herein are acidic compositions (eg, pH <4). While not being limited by a particular theory, acidic compositions may increase the solubility of SNS-595 and desirable pharmaceutical properties (e.g., increase patient comfort by reducing less irritation at the delivery site). Bring the right balance.

In one embodiment, SNS-595 is administered by IV injection. The composition for parenteral administration can be an emulsion or a sterile solution. Use may be made with propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil or injectable organic esters such as ethyl oleate as solvent or vehicle. These compositions may also contain adjuvants, especially isotonic agents, emulsifiers, dispersants, stabilizers, wetting agents.
Sterilization can be performed in several ways, for example using a bacterial filter, by radiation, or by heating. They can also be prepared in the form of a sterile solid composition and dissolved in sterile water or any other sterile medium for injection at the time of use.

  The composition can also be an aerosol. For use in the form of a liquid aerosol, the composition is a solid composition that is dissolved in a stable sterile solution or non-pyrogenic sterile water at the time of use in a saline solution or any other pharmaceutically acceptable medium. Can be a thing. For use in the form of a dry aerosol intended to be directly inhaled, the active ingredient is finely divided and combined with a water-soluble solid diluent or medium such as dextran, mannitol or lactose.

The pharmaceutical composition can be used in the manufacture of individual single unit dosage forms. Pharmaceutical compositions and dosage forms comprise SNS-595 and one or more excipients.
Pharmaceutical compositions and dosage forms can also include one or more additional active ingredients. Examples of optional second (or further) active ingredients are disclosed herein.

  In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of SNS-595 and typically one or more pharmaceutically acceptable carriers or excipients. Including. The term “carrier” refers to a diluent, adjuvant (eg, Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. In certain embodiments, water is a carrier when the pharmaceutical composition is administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable drug 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 pharmacy and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel , Sodium stearate, glycerol monostearate, talc, sodium chloride, dry skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form includes, but is not limited to, the method by which the dosage form will be administered to the subject and the particular active ingredient within the dosage form. Depends on various factors not known in the art. The composition or single unit dosage form can also contain minor amounts of wetting or emulsifying agents or pH buffering agents, if desired.

Further provided herein are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient is degraded. Such compounds, referred to herein as “stabilizers” include, but are not limited to, antioxidants such as ascorbic acid, pH buffer or salt buffer.
Pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsions, powders, and the like. Such compositions and dosage forms include, in certain embodiments, purified or prophylactic or therapeutic agents, in purified form, together with a suitable amount of carrier to provide a form for proper administration to a subject. Includes a prophylactically or therapeutically effective amount. The formulation should suit 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 animal subjects or mammalian subjects such as subjects and human subjects.

  A pharmaceutical composition provided herein is formulated to be compatible with its intended route of administration. Examples of routes of administration include subcutaneous, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, inhalation, intranasal, transdermal, topical, transmucosal, intratumoral, bursa and rectal administration. Including but not limited to. In a specific embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, intranasal or topical administration to a human. In one embodiment, the pharmaceutical composition is formulated according to routine procedures for subcutaneous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.

Examples of dosage forms include liquid dosage forms suitable for parenteral administration to a subject; and sterile solids that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject (eg, Crystalline solid or amorphous solid).
The composition, shape, and type of dosage forms provided herein typically vary depending on their use. For example, a dosage form used for the initial treatment of a disease may contain one or more of the active ingredients it contains in larger amounts than a dosage form used for maintenance therapy of the same infection. Similarly, a parenteral dosage form may contain one or more of the active ingredients it contains in smaller amounts than the oral dosage form is used to treat the same disease or disorder. These and other methods in which the specific dosage forms encompassed herein will be altered from one another will be readily apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 20th ed. Mack Publishing, Easton PA (2000).

  In general, the components of the compositions provided herein are as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the amount of active agent. Supplied either separately or mixed together into unit dosage forms. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

Typical dosage forms provided herein comprise SNS-595 in the range of about 1 mg / m ² ~ about 75 mg / m ² daily or weekly, in a single daily single dose in the morning Or in divided doses throughout the day taken with food. Certain dosage forms provided herein have about 1, 3, 6, 9, 12, 15, 18, 21, 24, 27 or 30 mg / m ² of SNS-595.

(6.6.1 Parenteral dosage form)
Parenteral dosage forms can be administered to a patient by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since these administrations typically bypass the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or can be sterilized prior to administration to the patient. . Examples of parenteral dosage forms include solutions ready for injection, dry preparations ready to be dissolved or suspended in a pharmaceutically acceptable medium for injection, suspensions and emulsions ready for injection. , Not limited.

  Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include but are not limited to: distilled water USP for injection; aqueous media such as, but not limited to, sodium chloride injection, Ringer injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer injection; Water-miscible media such as but not limited to polyethylene glycol and polypropylene glycol; and non-aqueous media such as corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

  In addition, compounds that increase the solubility of one or more of the active ingredients disclosed herein can be incorporated into parenteral dosage forms. For example, cyclodextrin and its derivatives can be used to increase the solubility of the active ingredient. See, for example, US Pat. No. 5,134,127, which is incorporated herein by reference.

(6.6.2 Topical and mucosal dosage forms)
In certain embodiments, transdermal dosage forms, topical dosage forms, and mucosal dosage forms are provided herein.
The transdermal, topical and mucosal dosage forms provided herein are ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions or Including other forms, but not limited. For example, Remington's Pharmaceutical Chemistry, 20th Edition (Remington's Pharmaceutical Sciences, 20th ed.) Mack Publishing, Easton PA (2000) and Introduction to Pharmaceutical Dosage Form, 4th Edition (Introduction to Pharmaceutical Dosage Forms, 4th ed.), See Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissue in the oral cavity can be formulated as a mouthwash or as an oral gel. In addition, transdermal dosage forms include “reservoir-type” or “matrix-type” patches that are applied to the skin for a specific period of time to allow permeation of the desired amount of active ingredient. You can wear it.

  Suitable excipients (eg, carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed herein are known to those of skill in the pharmaceutical arts. Depending on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1 to form non-toxic and pharmaceutically acceptable solutions, emulsions or gels. , 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures thereof. A moisturizer or wetting agent can also be added to pharmaceutical compositions and dosage forms as needed. Examples of such additional components are well known in the art. See, for example, Remington's Pharmaceutical Sciences, 20th ed. Mack Publishing, Easton PA (2000).

  The pH of the pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. In addition, compounds such as stearates can be added to pharmaceutical compositions or dosage forms to conveniently alter the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In this regard, stearate can serve as a lipid vehicle for the formulation, as an emulsifier or surfactant, and as a delivery enhancer or permeation enhancer. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.

(7. Examples)
Particular embodiments provided herein are illustrated by the following non-limiting examples.
(Example 1: Pharmaceutical composition suitable for injection or intravenous infusion)
Acidic compositions (<pH 4) are suitable for increased solubility of SNS-595 and desirable pharmacological properties (e.g., increased patient comfort by less irritation occurring at the delivery site). Brought a good balance. Illustrative examples of suitable compositions include: 10 mg SNS-595 per mL of 4.5% aqueous sorbitol adjusted to pH 2.5 with methanesulfonic acid. One protocol for making such a solution includes the following to make a 100 mg / 10 mL preparation: 100 mg SNS-595 and 450 mg D-sorbitol are added to distilled water; To a volume of 10 mL; adjust the pH of the resulting solution to 2.5 with methanesulfonic acid. The resulting composition is also suitable for lyophilization. The lyophilized form is then reconstituted with sterile water to an appropriate concentration prior to 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 escalation studies. As shown below, SNS-595 provides an excellent safety profile and evidence of antitumor activity in patients with refractory solid tumors.
SNS-595 was administered as an IV infusion over 10 minutes on two schedules to patients with advanced solid cancer. In the first schedule (A), a weekly dose of SNS-595 was administered for 3 weeks, followed by a rest of at least 7 days (qwk × 3). In the second schedule (B), the SNS-595 dose was administered once every 3 weeks (q3wk).

In both schedules, the starting dose of SNS-595 was 3 mg / m ² and the dose was increased by three series cohorts. The dose was doubled up to the first related adverse event of grade 2 or higher, or to the first abnormal laboratory lab value. The dose was then increased with a modified Fibonacci schema.
Within 42 days of the study, no other therapy was given, such as mitomycin-C, BCNU, nitrosourea drugs or Mab therapy.

In Study A, 21 patients (9 males, 12 females) were treated in 6 cohorts (dose range 3-24 mg / m ² / week). In Study B, 41 patients (25 men, 16 women) were treated in 9 cohorts (dose range 3-75 mg / m ² / week). Median age is 61 years (Study A) and 59 years (Study B), gender 12F / 9M (Study A) (16F / 25M (Study B), and all patients have baseline European cooperative tumors. With a European Cooperative Oncology Group Performance Status (ECOG PS) of 0-2, patient eligibility included refractory solid tumors and appropriate organ function. Provide patient demographics.

スケジュールAに従って投薬した患者について、PK試料を治療の1日及び15日目に収集し、非区画化解析を使用してアッセイした。血漿SNS-595濃度は、確認LC-MS／MSアッセイ法を使用して決定した。AUC(曲線下の領域)は、用量及び平均AUC_infに比例して増加し、3〜24mg/m²用量レベルについて、それぞれ1.7及び15μg* hr/mlの間で変動した。末端半減期は、およそ19時間である。薬物動態学的パラメーターの薬物依存的変化の証拠は、3回の毎週の服用後には観察されなかった。図1は、種々の患者コホート間の全時間にわたるSNS-595の血漿濃度を示す。表3は、スケジュールAに従って服用後の患者についての薬物動態学的パラメーターを提供する。 Table 2 provides a list of tumor types treated in both studies.

For patients dosed according to schedule A, PK samples were collected on days 1 and 15 of treatment and assayed using non-compartmental analysis. Plasma SNS-595 concentration was determined using a validated LC-MS / MS assay. AUC (area under the curve) increased in proportion to dose and mean AUC _inf and varied between 1.7 and 15 μg * hr / ml for 3-24 mg / m ² dose levels, respectively. The terminal half-life is approximately 19 hours. No evidence of drug-dependent changes in pharmacokinetic parameters was observed after 3 weekly doses. FIG. 1 shows the plasma concentration of SNS-595 over time between various patient cohorts. Table 3 provides pharmacokinetic parameters for patients after taking according to Schedule A.

For patients taking schedule B, pharmacokinetic parameters were set to 36 patients after a single dose of ³ to 75 mg / m2 (21 were pre-treated many times, 15 were pre-minimized Treated). Clearance (CL), distribution and terminal half-life (T _1/2 ) remained unchanged in all patients up to 48 mg / m ² . In minimally pretreated patients, PK parameters remained unchanged up to 75 mg / m ² . CL is 2.2L / hr / m2 (range 1.0~3.8L / hr / m ^2), volume of distribution is 53L / m ² (range 31~76L / m ^2), T _1/2 Was approximately 21 hours (range 13-49 hours). Exposure was similar for both pre-treated and minimally pre-treated patients and increased linearly to a dose of 48 mg / m ² . Exposure to minimally pretreated patients showed higher doses than linear AUC (area under the curve) at the 60 mg / m ² dose level. Table 4 shows the pharmacokinetic parameters for patients taking according to Schedule B.

研究Aでは、薬物動態を1日及び15日目(最初の服用及び3度目の服用後)に評価した。表5において分かるとおり、SNS-595は、再現性高い薬物動態及び低い患者間のばらつきを示す。薬物動態学的パラメーターの蓄積又は変化は、繰り返し投薬後に観察されなかった。曝露は、8倍の用量範囲(1.6〜15μg・hr/mL)にわたって直線的に増加して、クリアランス(CL)、分布量(Vss)及びT_1/2は、それぞれ2L/hr/m²、48L/m²、19時間の平均であり、1日から15まで変化しなかった。

In Study A, pharmacokinetics were evaluated on days 1 and 15 (first and third dose). As can be seen in Table 5, SNS-595 exhibits highly reproducible pharmacokinetics and low variability between patients. No accumulation or change in pharmacokinetic parameters was observed after repeated dosing. Exposure increases linearly over the 8-fold dose range (1.6-15 μghr / mL), with clearance (CL), distribution (Vss) and T _1/2 of ² L / hr / m ² , respectively 48L / m ² , an average of 19 hours, unchanged from day 1 to 15.

In Study B, pharmacokinetics were assessed 1 day after the first dose; exposure increased linearly over the 24-fold dose range (1.1-465 μg · hr / mL), with CL, Vss and T _1/2 Were the average of ² L / hr / m ² , 53 L / m ² and 21 hours, respectively.

Average pharmacokinetic parameters are provided in Table 5 for both studies.

FIG. 11 demonstrates dose linearity in studies A and B.
Table 6 provides data on the hematological effects observed in the study.

  In the description herein, the term “maximum tolerated dose” or “MTD” refers to a dose level below the dose of SNS-595 in which ≧ 2 of 6 patients experienced dose-limiting toxicity (DLI). Say. Patients who have been "pre-treated many times" or "HP" have previously had> 6 alkylating agents, chemotherapy courses, or> 2 platinum, mitomycin C or any nitrosourea courses Patients who have received or XRT> 25% of bone. The term “minimally pre-treated” or “MP” patient refers to a patient who does not meet the HP definition. (See Tolcher et al., JCO 2001; 19: 2937-2947).

  Dose-limited toxicity (DLI) as used herein is absolute neutrophil count (ANC) ≦ 500 for ≧ 7 days or febrile neutropenia or platelet nadir <25000 or bleeding or non-blood Adverse Events (AE) Grade 3 (as described in Common Terminology Criteria for Adverse Events Version 3.0: CTCAE v3.0) > 14 days needed to delay taking.

Tables 7-9 provide safety data for both studies.

As can be seen from the data, neutropenia was dose limiting toxicity (DLT) for both studies. In Study A, dose limiting toxicity (DLT) for neutropenia was seen in the first patient at the 24 mg / m ² level. Five patients were then treated with 18 mg / m ² and two developed neutropenic DLT. In Study B, a dose-limited toxicity (DLT) consisting of Grade 4 neutropenia was observed at 60 mg / m ² for more than 7 days in patients who had been previously treated. For patients treated in advance to a minimum, dose-limiting toxicity was dose Nitemi of 75 mg / m ^2.

The MTD for study A was 15 mg / m ² ; the MTD for study B was 48 mg / m ² for patients who had been pretreated many times (HP) and minimally pretreated ( MP) was 60mg / m ² for the patient.
For both studies, two patients had grade 4 thrombocytopenia; non-hematological toxicity was mostly grade 1/2 without dose-limited gastrointestinal or neurotoxicity.

  Table 10 provides evidence of clinical activity of SNS-595 for both studies. For Study A, the best responses included 1 patient who achieved a partial response (PR) and 6 who achieved a stable disease SD (range 16-24 weeks). For Study B, the best responses included 1 PR and 11 SDs (range 18-58 weeks). Table 11 provides details of partial / minority responses (PR / MR) in both studies.

Significantly, SNS-595 is a patient with advanced solid cancer, including 2 patients achieving partial response and 17 patients achieving stable disease for over 16 weeks Evidence for clinical activity in
As can be seen from the data, SNS-595 was well tolerated and showed clinical activity both at once weekly and once every 3 weeks dose. The dose limiting toxicity was non-cumulative neutropenia. SNS-595 showed predictable pharmacokinetics with low inter-patient and intra-patient variability. No pharmacokinetic parameter variability was observed after repeated dosing.
Useful doses for the treatment of solid tumors in a patient in need thereof, as described in this example, includes a 3 once week 48 mg / m ² and weekly 15 mg / m ^2.

(Example 3: High content screening and microscopic observation)
Cells were plated as a subconfluent population and allowed to grow for 36 hours. The cells were then treated with the compound at the given concentration for the given time. Cells were fixed using 4% formaldehyde and permeabilized with 0.1% Triton. Cells were exposed to primary antibodies for 1 hour at 25 ° C., 1: 100 dilution in 10% FBS / PBS (anti-pATM-Chemicon, anti-gH2AX-Cell Signaling Teclmology). Cells were exposed to secondary antibody for 1 hour in 10% FBS / PBS at 1: 100 dilution at 25 ° C. Hoechst staining was performed in 10% FBS / PBS at a concentration of 500 ng / ml. High content screening was performed on a Cellomics Arrayscan instrument using the Spot Detector algorithm.

  FIG. 2 shows HCT116 cells dosed with various compounds during a 6 hour period. Cells were then fixed and analyzed for protein phosphorylation status (gH2AX images obtained using a fluorescence microscope, pATM images obtained with ArrayScan VTi). As shown in the figure, nuclear foci formation is caused by SNS-595 treatment.

  Figures 3-5 illustrate the dependence of lesion formation on dose and time. The cells were then fixed and analyzed for phospho ATM. Cellornics Arrayscan software was used to identify the lesions (Figure 3, orange dots). Focal quantification was performed by measuring either focal fluorescence intensity (FIG. 4) or cells with more than two lesions (FIG. 5) as a function of time and SNS-595 concentration.

(Example 4: MTT assay and sensitization treatment)
Cells were plated at 4000 cells per well of a 96 well plate and incubated for 24 hours, then treated with compound for 72 hours. Cells were then incubated with 5% MTT for 1-2 hours to lyse. The MTT was read at 570 nm with a colorimeter and the EC ₅₀ was determined using linear regression analysis.

Sensitization was performed by various chemical treatments. Cells were pretreated with chemical sensitizer for 16 hours prior to drug addition (concentrations were as follows: caffeine, 2 mM, DNAPK inhibitor II (preparation), 10 μM and wortmannin, 100 nM). Data is provided in Table 12. Sensitization was measured as the fold decrease in EC ₅₀ for cytotoxicity as measured by MTT assay.

  The data show that SNS-595 shows a unique PIKK dependence. ATM / ATR and DNAPK are activated following treatment with SNS-595 for both therapies, but only DNAPK is required for DNA repair, and cells are only SNS if DNAPKcs activity is attenuated. -595 sensitized to antigen. ATM / ATR mediates G2-checkpoint outages. Loss of G2-checkpoint does not sensitize cells to SNS-595. In contrast to SNS-595, all other DSB inducers tested show sensitization using ATM / ATR for repair when either ATM or DNAPK activity is inhibited .

(Example 5: Repair of DNA damage in the absence of DNA damage detection kinase ATM and ATR)
HCT-l16 cells were treated with 10 mM SNS-595 or 10 mM etoposide for 6 hours in the presence or absence of 2 mM caffeine. The compound was then removed and the cells were allowed to recover for 16 hours. Cells were analyzed for gH2AX lesions before and after drug washout. As shown in FIG. 6, DNA damage induced by SNS-595 is easily repaired in the absence of ATM and ATR. In contrast, other drugs (eg, etoposide) utilize ATM and ATR for DNA repair. Caffeine treatment inhibits ATM and ATR activity, causing homologous recombination, nucleotide excision repair and mismatch repair defects.

Example 6: Repairing in DNA damage in the absence of DNA-damage detecting kinase DNA-PK
MO59K (wt) and MO59J (DNAPKcs (− / −)) cells were treated with 10 mM SNS-595 or 10 mM etoposide for 6 hours. The compound was then removed and the cells were allowed to recover for 16 hours. Cells were analyzed for gH2AX lesions before and after drug washout. As shown in FIG. 7, SNS-595 damage is not efficiently repaired in the absence of DNA-PK. In comparison, damage induced by other drugs other agents (eg, etoposide) is easily repaired.

(Example 7: Combination study with SNS-595)
Cell lines and cell cultures: HCT116 and NCI-H460 cell lines were obtained from ATCC. SKOV3 (p53-/-) and SKOV3 (p53 + / +) were obtained from Dr. George Stark's laboratory at Lerner Cleveland Clinic Institute. All cell lines were cultured in RPMI medium supplemented with 10% FBS, 1% sodium bicarbonate solution and 1% antibiotic (Cellgro).

MTT assay: Cells were plated at 4000 cells per well in a 96-well plate (plated at 8000 cells per well except SKOV3 (p53-/-)), incubated for 24 hours, then compounded Processed. Compound treatment lasted 72 hours. Cells were then incubated with 5% MTT for 1-2 hours to lyse. MTT was read with a colorimetric quantifier at 570 nm. The dead cell fraction was determined by the following formula:
Dead cell fraction = 1- [absorbance of sample well-average (absorbance of control without cell)] / [average (absorbance of control without DMSO) -average (absorbance of control without cell)]

Scheduling study: When the compound was dosed on a schedule with a washout, the cells were washed with 100 μl of fresh warm medium for 30 minutes, followed by a further wash after 90 minutes.
Statistical analysis: The data (fraction of dead cells) is analyzed using Calculsyn.V2 (Biosoft) and as the value of Combination Index at Fraction affected (Fa) = 0.5 It is shown in All data is shown with error bars indicating 95% confidence intervals for the mean.

  A combination is said to be additive if it yields a combination index between 0.85 and 1.2. A combination is said to be synergistic if it yields a combination index less than 0.85, and a combination is said to be antagonistic if it yields a combination index greater than 1.2. See Figures 8-10.

  As shown in FIGS. 8a-8d, SNS-595 dosed simultaneously with various cytotoxicity in HCT116 colon carcinoma cell lines (8a, 8b and 8c) and H460 lung cancer cell line (8d) was significantly synergistic. Or at least an additive combination index. As shown in Figure 9, SNS-595 dosed simultaneously with the selection of DNA damaging agents and antimetabolites showed a significant change in the combination index between SKOV3 ovarian cancer cell lines with or without p53 expression. There wasn't.

  As shown in FIGS. 10a-10d, SNS-595 co-medicated SNS-595 with docetaxel in HCT116 colon carcinoma cells (see FIGS. 10a and 10c) and gemcitabine (see FIGS. 10b and 10d) Or may have been antagonistic when dosed with a 24-hour delay. Antagonism is the first SNS-595 dosing (see FIGS. 10c and 10d, see the simultaneous dosing and 24 hours) for the first other drug dosing (see FIGS. 10a and 10b, see FIG. 24 hours). When cells are first treated with a drug, washed, and then treated with a second drug (see Figures 10a-d, 2 hour wash and 24 hour wash), additive or possibly synergistic effects Achieved.

(Example 8: MTT cell viability measurement-leukemia cells)
The following cell lines were used in this assay: HL-60 promyelocytic leukemia); Jurkat (T cell leukemia); CCRF-CEM (lymphoblastic leukemia); CEM / C2 (CCRF-CEM Camptothecin resistant derivatives).

Cells were seeded at 3000 cells per well of a 96 well plate and incubated for 16 hours. Compound dilutions were made in DMSO from 10 mM to 3 fold dilutions. Titration was diluted 1: 100 in the medium to achieve the final compound concentration. A 96-well plate was aspirated and compound dilutions in medium were added (100 ml / well). MTT analysis was performed after 72 hours incubation at 37 ° C. Briefly, 20 ml of MTT solution was added to each well. Cells were incubated for 1-2 hours at 37 ° C. Cells were lysed by addition of 100 ml / well cell lysis buffer and MTT was solubilized overnight at 37 ° C. The plate was read by absorbance measurement at 570 nM on a spectromax apparatus. IC ₅₀ was calculated using regression analysis with GraphPad Prism (data provided in Table 13). As provided in Table 13, SNS-595 exhibits a potent growth inhibitory effect on the tested blood cell lines.

(Example 9: Xenotransplantation model)
LM3-Jck human malignant lymphoma tumor debris (2-3 mm square) was implanted subcutaneously into nude mice. Tumors were increased to approximately 7-14 mm in diameter. Mice received no treatment, irinotecan (100 mg / kg, IV, q4d x 3), doxorubicin (12 mg / kg, IV, single shot), etoposide (12 mg / kg, IV, q1d4x5) and SNS-595 (25 and 20 mg / kg, IV, q7dx 5) Corresponding to the treatment group. Tolerable toxicity was defined as less than the toxic death of 1 of 6 treated animals with a mean group weight loss of 30% or less. The antitumor activity of the drug was evaluated 21 days after the start of administration.

  A 2-3 mm square CCRF-CEM acute lymphoblastic leukemia tumor debris was implanted subcutaneously in nude mice. Tumors were increased to approximately 8-20 mm in diameter. Mice received no treatment, irinotecan (100 mg / kg, IV, q4d x 3), doxorubicin (12 mg / kg, IV, q7d x 3), etoposide (12 mg / kg, IV, q1dx5) and SNS-595 (25 and 20 mg / kg, IV, q7d x 5) Corresponding to the treatment group. Tolerable toxicity was defined as less than the toxic death of 1 of 6 treated animals with a mean group weight loss of 30% or less. The antitumor activity of the drug was evaluated 20 or 21 days after the start of administration. Table 14 provides data on tumor inhibition (TI) and survival in CCRF-CEM and LM3-Jck xenograft models.

  As can be seen from the data in Table 14, SNS-595 administered at 20 and 25 mg / kg shows potent antitumor activity with complete tumor regression against LM-3 Jck malignant lymphoma. The SNS-595 tumor inhibition rate (IR) was similar to that of irinotecan and exceeded etoposide and doxorubicin in both CCRF-CEM and LM3-Jck xenograft models.

(Example 10: Bone marrow / cytodiagnosis assay)
Female CD-1 mice were administered intravenously 5, 10, 15 or 20 mg / kg SNS-595 on days 0 and 4. For hematological analysis, blood was drawn at 6, 8 and 12 days after the first injection. Femurs were removed on day 6 and fixed in Heck and stained with H & E prior to myeloid cell analysis. Two days after the second dose of SNS-595, bone marrow isolated from the femur showed a cellular dose-dependent decrease. Cellularity decreased to 7.5% at 20 mg / kg, while circulating neutrophils decreased from a pre-dose level of 1244 ± 55 cells / mL to the lowest point of 51 ± 24 cells / mL blood on day 8 did. The absolute neutrophil count then rebounded and soon returned to normal levels. Total WBC also reached the lowest point on day 8, but returned to normal levels. A dose-dependent decrease in hematopoietic myeloid cells is shown in FIG. The figure shows cellularity in the bone marrow 6 days after the first injection of SNS-595 at various doses.

FIG. 15 shows neutrophil counts from blood samples at 4, 6, 8, and 12 days after the first injection. As shown in FIG. 16, all SNS-595 dose groups showed a significant decrease in peripheral neutrophils by 8 days. As shown in FIG. 17, animals receiving 20 mg / kg SNS-595 injection had less than 50 cells / ml on day 8.
FIG. 18 shows that there is a mild platelet response on day 8 versus SNS-595 injection. FIG. 19 shows the rate of change in body weight at various time points after SNS-595 administration. FIG. 20 shows bone marrow rebounded 12 days after injection of 20 mg / kg SNS-595.

(Example 11: Clinical trial data of SNS-595 in patients with hematological malignancy)
SNS-595 was administered as a slow IV push to patients with advanced or refractory acute leukemia. Diagnosis included AML (19 patients) and ALL (2 patients). All patients were disease refractory to the previous therapy or relapsed from the previous therapy (median 3 before prescribing plan (range 1-6)).

A total of 21 patients (9 women and 12 men; median age = 64 years, range 21-80) were treated in 5 cohorts using 2 schedules. In the first schedule (A), a weekly dose of SNS-595 was administered for 3 weeks followed by a 7-day rest (qwk x3). In the second schedule (B), the dose of SNS-595 was administered twice a week for 2 weeks (biwk x2). The cycle period, including the days of break, was 28 days for both schedules. Schedule A had a total of 3 doses per cycle and Schedule B had a total of 4 doses per cycle. If the patient achieved stable disease or more, further cycles were allowed. The starting dose was 18 mg / m ^{2 for} Schedule A and 9 mg / m ² for Schedule B, and the dosage was increased by the cohort. Three to six patient cohorts were obtained at doses using a modified Fibonacci sequence.

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

Plasma SNS-595 concentration was determined using a validated LCM / MS assay. Plasma exposure at the first two dose levels for each schedule increased linearly, yielding 4.3 to 17.8 μghr / mL AUC for the 9 to 27 mg / m ² dose. CL, Vss and terminal half-life were similar to those in solid tumor patients and averaged ˜2 L / hr / m ² , 58 L / m ² and 23 hours, respectively. Six patients distributed across all dosage groups shown in Table 15 experienced more than 50% reduction in peripheral blasts after cycle 1.

No toxic dose limit (DLT) was observed up to 27 mg / m ^{2 on} the qwk x3 schedule or 13.5 mg / m ^{2 on the} biwk x2 schedule. Non-toxic limited doses included nausea / vomiting, diarrhea and mucositis. Grade 4 neutropenic fever was observed in only one patient.
The other patient cohort, according to the schedule A (qwk x3), was administered at each dose of 38 mg / m ² and 50 mg / m ^2. More cohort of other patients, according to the schedule B (biwk x2), was administered at each dose of 19 mg / m ² and 25 mg / m ^2. Safety data is shown in Table 16.

Useful dosing schedules for treatment of hematologic malignancies, can comprise about 50 mg / m ² ~ about 80 mg / m ² administered once a week during 3 weeks. Another dose that finds use in the treatment of hematological malignancies is about 55 mg / m ² to about 75 mg / m ² administered weekly during the week. Other doses that find use in the treatment of hematological malignancies include 60, 65, 70 or 75 mg / m ² administered weekly during the week.

Other dosing schedules useful for treatment of patients with hematologic malignancies, can comprise about 25 mg / m ² ~ about 50 mg / m ² administered twice a week during 2 weeks. To another dose finding use in the treatment of hematologic malignancies, between two weeks is about 30 mg / m ² ~ about 45 mg / m ² administered twice a week. Other doses that find use in the treatment of hematological malignancies include 30, 35, 40, or 45 mg / m ² administered twice a week for 2 weeks.

  The above-described embodiments of the present invention are intended to be illustrative only and those skilled in the art will recognize numerous equivalents of specific compounds, materials and procedures using only routine testing. Will be or could be confirmed. All such equivalents are considered to be within the scope of the invention and are covered by the appended claims.

(4. Brief description of drawings)
FIG. 1 shows the plasma concentration of SNS-595 over a period of time between various patient cohorts dosed on a qwk × 3 schedule. FIG. 2 illustrates nuclear foci formation in HCT116 cells after treatment with SNS-595, etoposide, bleomycin and cisplatin. FIG. 3 shows lesion quantification by measuring lesion fluorescence intensity. FIG. 4 illustrates the dependence of lesion formation on dose and time. FIG. 5 shows cells of more than 2 lesions as a function of time and SNS-595 concentration. FIG. 6 illustrates DNA damage induced by SNS-595 and etoposide in the presence or absence of caffeine, an inhibitor of ATM and ATR. FIG. 7 shows DNA damage induced by SNS-595 and etoposide in the presence (MO59K cells) and absence (MO59J cells) of DNA-PK. FIGS. 8a-c demonstrate the synergy / additive effect of co-medication SNS-595 with various cytotoxic agents in HCT 116 colon carcinoma cells. FIG. 8d demonstrates the synergy / additive effect of co-medication SNS-595 with various cytotoxic agents in H460 lung cancer cells. FIG. 9 shows the combination index when SNS-595 is dosed simultaneously with the selection of DNA damaging agents and antimetabolites in SKOV3 ovarian cancer cell lines (+ / +) and (− / −) for p53 expression. Yes, shown as black and gray diamonds, respectively. FIGS. 10a-d demonstrate the effect of co-administering various cytotoxic agents and SNS-595 on HCT 116 colon carcinoma cells. FIG. 11 shows dose linearity of 3 weekly doses of SNS-595 (qwk x3; circle = 1 week; triangle = 2 weeks) and once every 3 weeks (q3wk; diamond) in patients with advanced solid tumors. I will provide a. FIG. 12 provides a comparison of the antitumor activity of SNS-595, etoposide, doxorubicin and irinotecan in a CCRF-CEM xenograft model. FIG. 13 provides a comparison of the antitumor activity of SNS-595 (at 20 mg / kg and 25 mg / kg), etoposide, doxorubicin and irinotecan in the LM3-Jck xenograft model. FIG. 14 shows cellularity in bone marrow 6 days after the first injection of SNS-595 in female CD-1 mice. SNS-595 was administered on days 0 and 4. All images are shown at 10x magnification. FIG. 15 provides neutrophil response to SNS-595 dose. FIG. 16 provides neutrophil counts at various SNS-595 doses up to 8 days. FIG. 17 provides WBC counts at various SNS-595 doses up to 8 days. FIG. 18 provides platelet counts at various SNS-595 doses up to 8 days. FIG. 19 provides weight gain and loss rates at various time intervals after SNS-595 administration. FIG. 20 shows bone marrow recoil up to 12 days after administration of 20 mg / kg SNS-595.

Claims (13)

A pharmaceutical composition for treating acute myeloid leukemia in a human, comprising 50 mg / m ² ~ 90mg / m ² (+)-1,4-dihydro-7-[(3S, 4S) -3-methoxy-4- (methylamino) -1-pyrrolidinyl] -4-oxo- The pharmaceutical composition comprising 1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid. Whether the acute myeloid leukemia recurs or is refractory to a therapy selected from surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, immunotherapy, blood transfusion and combinations thereof ; or resistant pharmaceutical composition of claim 1. Wherein the dose is ^{50mg / m 2 ~80mg / m 2} , it is for administration once a week, according to claim 1 or 2 pharmaceutical composition. Wherein the dosage is ^{55mg / m 2 ~75mg / m 2} , The pharmaceutical composition of claim 1. The pharmaceutical composition according to claim 4 , wherein the dose is 60 mg / m ² . Wherein the dosage is 65 mg / m ^2, claim 4 pharmaceutical composition. The pharmaceutical composition according to claim 4 , wherein the dose is 70 mg / m ² . Wherein the dosage is 75 mg / m ^2, claim 4 pharmaceutical composition. The pharmaceutical composition according to any one of claims 3 to 8 , which is for administration once a week for 3 weeks. Is for administration twice weekly, The pharmaceutical composition of claim 1. It is for administration for two weeks, The pharmaceutical composition of claim 1. The pharmaceutical composition according to any one of claims 1 to 11 , which is for IV injection. It is for administration by IV push 10-15 minute period, The pharmaceutical composition of claim 1.

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