Indian Patents. 254943:PHARMACEUTICAL COMPOSITIONS COMPRISING (+)-1,4-DIHYDRO-7-[(3S,4S)-3-METHOXY-4-(METHYLAMINO)-1-PYRROLIDINYL]-4-OXO-1-(2-THIAZOLYL)-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID

Title of Invention	PHARMACEUTICAL COMPOSITIONS COMPRISING (+)-1,4-DIHYDRO-7-[(3S,4S)-3-METHOXY-4-(METHYLAMINO)-1-PYRROLIDINYL]-4-OXO-1-(2-THIAZOLYL)-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID
Abstract	Abstract The present invention relates to SNS-595 and methods of treating cancer using the same. Figure 1 depicts the plasma concentrations of SNS-595 over time among the various patient cohorts.

Full Text	SNS-595 AND METHODS OF USING THE SAME SNS-595 is novel naphthyridine cytotoxic agent that was previously known as AG-7352 (see e.g., Tsuzuki et al, Tetrahedron-Asymmetry 12: 1793-1799 (2001) and U.S. Patent No. 5,817,669). The chemical name of SNS-595 is (+)-l,4-dihydro-7-[(3s,4s)-3-methoxy-4- (methylamnio)-l-pyrroledinyl]-4oxo-1-(2-thiaoyl)-1,8-naphthyridine-3-carboxylic acid and has the structure shown below The present invention relates to pharmaceutical compositions and methods of using SNS-595 to treat cancer. DESCRIPTION OF THE FIGURES Figure 1 depicts the plasma concentrations of SNS-595 over time among the various patient cohorts. DETAILED DESCRIPTION In one aspect of the present invention, pharmaceutical composition is provided comprising: a) SNS-595 and b) an acid in an aqueous solution wherein the pH of the solution is 2-3.5. As used herein, a numerical range is intended to be inclusive. For example, the range of pH 2-3.5 includes both pH 2 and pH 3.5. In one embodiment, the pH of the composition is 2-3. In another embodiment the pH of the composition is 2.3-2.7. As used herein, an aqueous solution is a liquid comprising water. Suitable examples of acids include both organic and inorganic acids such as acetic acid ascorbic acid, benzene-sulfonic acid, ethanesulfonic acid, glycolic acid, hydrogen chloride. hydrogen bromide, hydroxyethanesulfonic acid, lactic acid, maleic acid, methanesulfonic acid, proprionic acid, succinic acid, sulfuric acid, trifluoroacetic acid, and toluenesulfonic acid. In one embodiment, the acid is hydrochloric acid, methanesulfonic acid or lactic acid. In another embodiment, the acid is methanesulfonic acid. In another embodiment, the pharmaceutical composition further comprises a tonicity agent. Suitable examples of a tonicity agent include amino acids (e.g., alanine and glycine), electrolytes (e.g., sodium chloride and potassium chloride), monosaccharides (e.g. glucose or galactose), disaccharides (e.g. sucrose) and hexahydric alcohols (e.g., mannitol and sorbitol). In another embodiment, the tonicity agent is sodium chloride, glucose, mannitol, or sorbitol in another embodiment, the tonicity agent is a hexahydric alcohol. In another embodiment, the tonicity agent is sorbitol. SNS-595 is a cytotoxic agent for the treatment of cancer. The types of cancers that can be treated using the inventive methods include but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer (both small cell and non-small cell), lymphoma, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. hi another aspect of the invention, a method of using SNS-595 to treat a human cancer is provided. The method comprises administering to a patient on the basis of body surface area, a dose of 10 mg/m2-150 mg/m2 of SNS-595. Body surface area calculations can be calculated for example, with the Mosteller formula wherein: BSA (m2) = square root of [(height (cm) x weight (kg)/3600]. In another embodiment, the dose is 10 mg/m2-100 mg/m2. In another embodiment, the dose is 30 mg/m2-75 mg/m2. in axiother embodiment, the dose is 40 mg/m2-80 mg/m2. In another embodiment, the dose is 50 mg/m -90 mg/m . In another embodiment the dose is 20 mg/m2-30 mg/m2-. In another embodiment the dose-is 25 mg/m2-35 mg/m2. In another embodiment the dose is 40 mg/m2-50 mg/m2. In another embodiment the dose is 45 mg/m2-55 mg/m2. in another embodiment the dose is 50 mg/m--60 mg/m . In another embodiment the dose is 55 mg/m -65 mg/m . In another embodiment the dose is 60 mg/m -70 mg/m . In another embodiment the dose is 65 mg/m -75 mg/m". In another embodiment the dose is 70 mg/m2-80 mg/m2. In another embodiment the dose is 75 mg/m2-85mg/m". In another embodiment the dose is 80 mg/m2-90 mg/m . In another embodiment the dose is 85 mg/m2-95 mg/m2. In another embodiment the dose is 90 mg/m2-I00 rng/m2. In another embodiment the dose is 95 mg/m -105 mg/m . In another embodiment the dose is 100 rng/m2-110 mg/m . In another embodiment the dose is 105 mg/m - 115 mg/m2. In another embodiment the dose is 110 mg/m2-120 mg/m . In another embodiment the dose is 115 mg/m2-125 mg/m2. In another embodiment the dose is 120 mg/m2-130 mg/m2. In another embodiment the dose is 125 mg/m2- 135 mg/m . In another embodiment the dose is 130 mg/m - 140 mg/m 2. In another embodiment the dose is 135 mg/m2 -145 mg/m2 . In another embodiment the dose is 140 mg/m"-150 mg/m2. The administered dose of SNS-595 can be delivered simultaneously (e.g. a single bolus injection) or over a 24-hour period (e.g., continuous infusion over time or divided bolus doses over time) and is repeated until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. For example, stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more firom the last measurement. See e.g., Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3): 205-216 (2000). Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities. The administered dose of SNS-595 can be expressed in units other than as mg/m . For example, doses can be expressed as mg/kg. One of ordinary skill in the art would readily know how to convert doses from mg/m2 to mg/kg to given either the height or weight of a subject or both (see e.g., http:///www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 10 mg/m2 -150 mg/m2 for a 65 kg human is approximately equal to 0.26 mg/kg-3.95 mg/kg. In another aspect of the present invention, SNS-595 is administered according to a dosing schedule. In one embodiment, the method comprises: i) administering a dose of 10 mg/m2-l 50 mg/m2 of SNS-595 to a patient; ii) waiting a period of at least one day where the subject is not administered any SNS-595; iii) administering another dose of 10 mg/m2-150 mg/m2 of SNS-595 to the patient; and, repeating steps ii)-iii) a plurality of times. For example, if the waiting period were 6 days, then the initial dose of SNS-595 is administered on Day 1 (step i); the waiting period is six days (step ii); and the following dose of SNS-595 is administered on Day 8 (step iii). Other exemplary time periods include 2 days, 3 days, 13 days, 20 days, and 27 days. In another embodiment, the waiting period is at least 2 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 6 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 6 days and steps ii) through iii) are repeated at least five 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) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 27 days and steps ii) through 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 five times. In another embodiment, the dosing method comprises administering a weekly dose of SNS-595 to a subject In another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every two weeks. In another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every three weeks, hi another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every four weeks. In another embodiment, the dosing method comprises a cycle wherein the cycle comprises administering a dose of SNS-595 to a subject every week for three weeks followed by a period of at least two weeks where no SNS-595 is administered to said subject and wherein the cycle is repeated a plurality of times. In another embodiment, the period where no SNS-595 is administered is two weeks. In another embodiment, the period where no SNS-595 is administered is three weeks. In another aspect of the invention, a method of treating a solid tumor is provided. The method comprises; i) administering a dose of 10 mg/m2-100 mg/m2 of SNS-595 to a patient; ii) waiting a period of at least six days where the subject is not administered any SNS-595; iii) administering another dose of 10 mg/m -100 mg/m2 of SNS-595 to the patient; and, iv) repeating steps ii)-iii) a plurality of times. In another aspect of the invention, a method of treating a hematologic cancer such as leukemias and lymphomas is provided. The method comprises: i) ,- administering a dose of 60 mg/m2-l 50 mg/m2 of SNS-595 to a patient; ii) waiting a period of at least two days where the subject is not administered any SNS-595; iii) administering another dose of 60 mg/m -150 mg/m2 of SNS-595 to the patient; and, iv) repeating steps ii)-iii) a plurality of times. In another aspect of the present invention, a method is provided supportive care to patients being treated with SNS-595. The method comprises: a) administering to a patient a dose of 10 mg/m -150 mg/m" of SNS-595 and b) administering a therapeutically effective amount of a supportive care agent. The supportive care agent is any substance that prevents or manages an adverse effect from SNS-595 treatment and is administered according to the appropriate dosing regimen for that substance. For example, different supportive care agents for treating nausea have different dosing regimen. While some are administered prophylactically, others are co-administered with SNS-595 while still others are administered after the administration of SNS-595. Illustrative examples of supportive care agents their doses and dosing regimens are found in The Physician's Desk Reference. In one embodiment, the supportive care agent is an antiemetic. Illustrative examples of antiemetics include but are not limited to phenothiazines, butyrophenones, benzodiazapines, corticosteroids, serotonin antagonists, cannabinoids, and NK) receptor antagonists. Examples of phenothiazine antiemetics include prochlorperazine and trimethobenzamide. An example of a butyrophenone antiemetic is haloperidol. An example of a benzodiazepine antiemetic is lorazepam. An example of a corticosteroid antiemetic is dexamethasone. Examples of a serotonin antagonist antiemetic include ondansetron, gramsetron, and dolasetron. An example of a cannabinoid antiemetic is dronabinol An example of an NKl receptor antagonist is aprepitant In another embodiment, the antiemetic is prochlorperazine. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is 10 mg. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is an oral dose of 10 mg before the administration of SNS-595. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is an oral dose of 10 mg every four to six hours as needed after the administration of SNS-595. In another embodiment, the antiemetic is dexamethasone. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is at least 4 mg. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is an oral dose of 4 mg before the administration of SNS-595. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is an oral dose of 8 mg before the administration of SNS-595. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is an intravenous dose of between about 10 mg and about 20 mg before the administration of SNS-595. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is an oral dose of 4 mg every six to twelve hours as needed after the administration of SNS-595. In another embodiment, the antiemetic is lorazepam. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is 1 mg. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an oral dose of 1 mg before the administration of SNS-595. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an intravenous dose of 1 mg before the administration of SNS-595. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an oral dose of 1 mg every four to six hours as needed after the administration of SNS-595. In another embodiment the antiemetic is dolasetron. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is 100 mg. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is an oral dose of 100 mg before the administration of SNS-595. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is an intravenous dose of 100 mg before the administration of SNS-595. In another embodiment the antiemetic is ondansetron. In another embodiment the antiemetic is ondansetron and the therapeutically effective amount is at least 10 mg. In another embodiment, the antiemetic is ondansetron and the therapeutically effective amount is an intravenous dose of 10 mg before the administration of SNS-595. In another embodiment the antiemetic is ondansetron and the therapeutically effective amount is an intravenous dose of 32 mg before the administration of SNS-595. In another embodiment the antiemetic is granisetron. In another embodiment the antiemetic is granisetron and the therapeutically effective amount is 10 μ ig/kg. In another embodiment the antiemetic is granisetron and the therapeutically effective amount is an intravenous dose of 10 μ g/kg before the administration of SNS-595. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is at least 1 mg. In another embodiment the antiemetic is granisetron and the therapeutically effective amount is an oral dose of 1 mg before the administration of SNS-595. In another embodiment the antiemetic is granisetron and the therapeutically effective amount is an oral dose of 2 mg before the administration of SNS-595. In another embodiment, the antiemetic is aprepitant. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is at least 80 mg. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is an oral dose of 125 mg before the administration of SNS-595. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is a daily oral dose of 80 mg for at least two days after the administration of SNS-595. In another embodiment, the supportive care agent is a hematopoietic agent. A hematopoietic agent is a molecule that stimulates hematopoiesis. Illustrative examples of hematopoietic agents include but are not limited to granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin and erythropoiesis stimulating protein, and derivatives thereof. Examples of G-CSF include but are not limited to filgrastim and its derivatives including pegfilgrastim. An example of GM-CSF includes sargramostim. An example of erythropoietin is epoetin alfa. An example of erythropoiesis stimulating protein is darbepoetin alia. In another embodiment, the hematopoietic agent is G-CSF. In another embodiment, the hematopoietic agent is filgrastim, hi another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is at least 4 μg/kg. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is a daily dose of at least 4 jig/kg for at least 7 days after the administration of SNS-595. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is a daily subcutaneous dose of between about 4 μg/kg and about 8 μg/kg for at least 7 days starting from the third day after the administration of SNS-595. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is a daily subcutaneous dose of between about 4 μg/kg and about 10 μg/kg for at least 14 days starting from the third day after the administration of SNS-595. In another embodiment, the hematopoietic agent is pegfilgrastim. In another embodiment the hematopoietic agent is pegfilgrastim and the therapeutically effective amount is 6 mg. In another embodiment, the hematopoietic agent is pegfilgrastim and the therapeutically effective amount is a daily subcutaneous dose of 6 mg after the administration of SNS-595. In another embodiment, the hematopoietic agent is pegfilgrastim and the therapeutically effective amount is 100 μg/kg. In another embodiment, the hematopoietic agent is pegfilgrastrm and the therapeutically effective amount is a daily dose of 100 ug/kg after the administration of SNS-595. In another embodiment, the hematopoietic agent is GM-CSF. In another embodiment, the hematopoietic agent is sargramostim. In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is 250 μg/m2. In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 μg/m2. In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 μg/m2 as needed starting from the third day after the administration of SNS-595. la another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 μg/m2 as needed starting from the tenth day after the administration of SNS-595. In another embodiment, the hematopoietic agent is erythropoietin. In another embodiment, the hematopoietic agent is epoetin alfa. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is at least 150 units/kg. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is an intravenous or subcutaneous dose of 150 units/kg three times a week after the administration of SNS-595. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is an intravenous or subcutaneous dose of 300 units/kg three times a week after the administration of SNS-595. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is 40,000 units. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is a weekly dose of 40,000 units after the administration of SNS-595. In another embodiment, the hematopoietic agent is erythropoiesis stimulating protein. In another embodiment, the hematopoietic agent is darbepoetin alfa. In another embodiment, the - hematopoietic agent is darbepoetin alfa and the therapeutically effective amount is between about 1.5 μg/kg and about 4.5 μg/kg. In another embodiment, the hematopoietic agent is darbepoetin alfa and the therapeutically effective amount is a weekly dose of between about 1.5 μg/kg and about 4.5 μg/kg. All cited references are incorporated herein by reference. EXAMPLE 1 Pharmaceutical composition suitable for injection or intravenous infusion Acidic compositions ( EXAMPLE 2 Pharmacokinetics of SNS-595 in cancer patients SNS-595 was administered to enrolled patients for up to six cycles. A cycle is defined as a three-week period, with SNS-595 administered on the first day of each cycle (day 0), followed by at least 21 days of observation. SNS-595 was administered to cohorts of at least 3 patients and dose escalation occurred by sequential cohort. Doses of SNS-595 were linear with AUC oo and its pharmacokinetic properties were remarkably consistent among patients in the same cohort. Figure 1 depicts the plasma concentrations of SNS-595 overtime among the various patient cohorts and Table 1 shows the pharmacokinetic parameters derived there from. What is claimed is: 1. A method for treating cancer comprising administering to a patient a dose of 10 mg/m2-150 mg/m2 of SNS-595. 2. The method of claim 1 wherein the dose is 10 mg/m -100 mg/m2. 3. The method of claim 1 wherein the dose is 30 mg/m2 -75 mg/m2. 4. The method of claim 1 wherein fee dose is 40 mg/m2-80 mg/m2. 5. The method of claim 1 wherein the dose is 50 mg/m2-90 mg/m2. 6. The method of claim 1 wherein the cancer being treated is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. 7. The method of claim 1 wherein the dose is 10 mg/m2-100 mg/m2 and the cancer being treated is a solid tumor. 8. The method of claim 1 wherein the dose is 60 mg/m -150 mg/m and the cancer being treated is a hematologic cancer. 9. The method of claim 1 additionally comprising administering to a patient a therapeutically effective dose of a supportive care agent. 10. The method of claim 9 wherein the supportive care agent is an antiemetic. 11. The method of claim 9 wherein the supportive care agent is a hematopoietic agent. 12. A method comprising: i) administering a dose of 10 mg/m 2-150 mg/m2 of SNS-595 to apatient; ii) waiting a period of at least one day where the subject is not administered any SNS-595; iii) administering another dose of 10 mg/m2-150 mg/m2 of SNS-595 to the patient; and, iv) repeating steps ii)-iii) a plurality of times. 13. The method of claim 12 wherein the waiting period is at least 2 days. 14. The method of claim 12 wherein the waiting period is at least 3 days. 15. The method of claim 12 wherein the waiting period is at least 6 days. 16. The method of claim 12 wherein the waiting period is at least 13 days. 17. The method of claim 10 wherein the waiting period is at least 20 days. 18. The method of claim 10 wherein the waiting period is at least 27 days 19. A method comprising administering a weekly dose of SNS-595 to a patient. 20. A method comprising administering a dose of SNS-595 to a patient every three weeks. 21. A method comprising a cycle wherein the cycle comprises administering a dose of SNS-595 to a subject every week for three weeks followed by a period of at least two weeks where no SNS-595 is administered to said subject and wherein the cycle is repeated a plurality of times. 22. A method for treating cancer comprising administering to a patient a dose of 10 mg/m2 -150 mg/m of SNS-595 and administering a patient a therapeutically effective dose of a hematopoietic agent. 23. The method of claim 22 wherein the hematopoietic agent is G-CSF. 24. The method of claim 22 wherein the hematopoietic agent is GM-CSF. 25. The method of claim 22 wherein the hematopoietic agent is erythropoietin. 26. The method of claim 22 wherein the hematopoietic agent is erythropoiesis stimulating protein. NEW CLAIMS 27. A use of SNS-595 in the manufacture of a composition for treating cance, wherein the composition is administered to a patient in a dose of 10 mg/ m2-150mg/ m2 of SNS-595. 28. The use of claim 27. wherein the dose is 10 rng/m2-100mg/m2. 29. The use of claim 27. wherein the dose is 30mg/ m2-75mg/ m2. 30. The use of claim 27. wherein the dose is 40mg/ m2-80rng/ m2. 31. The use of claim 27, wherein the dose is 50mg/ m2-90mg/ m2. 32. The use of claim 27, wherein the cancer being treated is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphom, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. 33. The use of claim 27. wherein the dose is 10mg/ m2-l00mg/ m2 and the cancer being treated is a solid tumor. 34. The use of claim 27. wherein the dose is 60 mg/ m2-150mg/ m2 and the cancer beins treated is a hematologic cancer. 35. The use of claim 27 additionally comprising administering to a patient a therapeutically effective dose of a supportive care agent. 36. The use of claim 35. wherein the supportive care agent is an antiemetic. 37. The use of claim 35, wherein the supportive care agent is a hematopoietic agent. 38. The use of SNS-595 in manufacturing a composition for use in a method comprising: i) administering a dose of 10mg/m2-150 mg/m2 of SNS-595 to a patient: ii) waiting a period of at least one day where the subject is not administered any SNS-595; iii) administering another dose of 10 mg/m2-l 50mg/m2 of SNS-595 to the patient: and iv) repeating steps ii) -iii) a plurality of times. 39. The use of claim 38. wherein the waiting period is at least 2 days. 40. The use of claim 38. wherein the waiting period is at least 3 days. 41. The use of claim 38, wherein the waiting period is at least 6 days. 42. The use of claim 38. wherein the waiting period is at least 13 days. 43. The use of claim 38. wherein the waiting period is at least 20 days. 44. The use of claim 38. wherein the waiting period is at least 27 days 45. The use of SNS-595 in manufacturing a composition for use in administering a weekly dose of SNS-595 to a patient. 46. The use of SNS-595 in manufacturing a composition for use in administering a dose of SNS-595 to a patient every three weeks. 47. The use of SNS-595 in manufacturing a composition for use in method comprising a cycle, wherein the cycle comprises administering a dose of SNS-595 to a subject every week for three weeks followed by a period of at least two weeks where no SNS-595 is administered to said subject and wherein the cycle is repeated a plurality of times. 48. The use of SNS-595 in manufacturing a composition for use in a method for treating cancer comprising administering to a patient a dose of 1 0mg/m2-150mg/m2 of SNS-595 and administering a patient a therapeutically effective dose of a hematopoietic agent. 49. The use of claim 48. wherein the hematopoietic agent is G-CSF. 50. The use of claim 48. wherein the hematopoietic agent is GK4-CSF. 51. The use of claim 48, wherein the hematopoietic agent is erythropoietin. 52. The use of claim 48. wherein the hematopoietic agent is erythropoiesis stimulating protein. 53. A pharmaceutical composition comprising (+)-l,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methy lam ino)-l -pyrrol id inylj-4-ox.o-l -(2-th iazoly I)-1,8-naphthyridine-3-carboxylic acid and an acid. 54. The pharmaceutical composition of claim 53 further comprising water. 55. The pharmaceutical composition of claim 53, wherein a pH of the composition is less than 4. 56. The pharmaceutical composition of claim 53, wherein the pH of the composition is between 2.3 to 2.7. 57. The composition of claim 53, wherein the acid is an organic or inorganic acid. 58. The composition of claim 57. wherein the acid is selected from acetic acid, ascorbic acid, benzenesulfonic acid, ethanesulfonic acid, glycolic acid, hydrogen chloride. hydrogen bromide, hydroxyethanesulfonic acid, lactic acid, maleic acid, methanesuifonic acid, proprionic acid, succinic acid, sulfuric acid, trifluoroacetic acid and toluenesulfonic acid. 59. The pharmaceutical composition of claim 53. wherein the acid is methanesuifonic acid. 60. The pharmaceutical composition of claim 53 further comprising a tonicity agent. 61. The pharmaceutical composition of claim 60. wherein the tonicity agent is selected from an amino acid, electrohte. monosaccharide, disaccharide and hexahydric alcohol. 62. The pharmaceutical composition of claim 60. wherein the tonicity agent is sorbitol. 63. The pharmaceutical composition of claim 53, wherein (+)-1,4-dihydro-7-[(3S.4S)- 3-methoxy-4-(methylamino)-l-pyrrolidinyI]-4-oxo-l-(2-thiazolyl)-l ,8-naphthyridine-3- carboxylic acid is present in an amount 10 mg/mL. 64. The pharmaceutical composition of claim 63. wherein the sorbitol is present in an amount 4.5%. 65. The pharmaceutical composition of claim 53. wherein the pH of the composition is 2.5. 66. The pharmaceutical composition of claim 53, wherein the composition comprises 1 00 rng of (-)-1.4-dihydro-7-[(3S.4S}-3-methoxy-4-(methyl,amino)-1 -pyrroiidinyI]-4-oxo-1 -(2- thiazolyl)-! .8-naphthyridine-3-carhoxylic acid and 450 mg of sorbitol per 10 mL of the composition. 67. A lyophilized powder comprising (+)-l ,4-dihydro-7-[(3S.4S)-3-methoxy-4- (methylamino)-] -pyrrolidinyI]-4-oxo-l -(2-thiazolyl)-1.8- naphthyridine-3-carboxylic acid and an acid. 68. An aqueous pharmaceutical composition comprising 100 mg of (+)-],4-dihydro- 7-[(3S,4S)-3-methoxy-4-(methy lam ino)-l-pyrrol idiny I]- 4-oxo-l -(2-th iazoly I)- 1.8-naphthy rid ine- 3-carboxylic acid and 450 mg of sorbitol per 10 mL of the composition, wherein the composition has a pH of 2.5 adjusted with methanesuifonic acid.

Full Text

SNS-595 AND METHODS OF USING THE SAME
SNS-595 is novel naphthyridine cytotoxic agent that was previously known as AG-7352 (see e.g., Tsuzuki et al, Tetrahedron-Asymmetry 12: 1793-1799 (2001) and U.S. Patent No. 5,817,669). The chemical name of SNS-595 is (+)-l,4-dihydro-7-[(3s,4s)-3-methoxy-4-
(methylamnio)-l-pyrroledinyl]-4oxo-1-(2-thiaoyl)-1,8-naphthyridine-3-carboxylic acid and has
the structure shown below
The present invention relates to pharmaceutical compositions and methods of using SNS-595 to treat cancer.
DESCRIPTION OF THE FIGURES
Figure 1 depicts the plasma concentrations of SNS-595 over time among the various patient cohorts.
DETAILED DESCRIPTION
In one aspect of the present invention, pharmaceutical composition is provided comprising:
a) SNS-595 and
b) an acid
in an aqueous solution wherein the pH of the solution is 2-3.5. As used herein, a numerical range is intended to be inclusive. For example, the range of pH 2-3.5 includes both pH 2 and pH 3.5. In one embodiment, the pH of the composition is 2-3. In another embodiment the pH of the composition is 2.3-2.7. As used herein, an aqueous solution is a liquid comprising water.
Suitable examples of acids include both organic and inorganic acids such as acetic acid ascorbic acid, benzene-sulfonic acid, ethanesulfonic acid, glycolic acid, hydrogen chloride.

hydrogen bromide, hydroxyethanesulfonic acid, lactic acid, maleic acid, methanesulfonic acid, proprionic acid, succinic acid, sulfuric acid, trifluoroacetic acid, and toluenesulfonic acid. In one embodiment, the acid is hydrochloric acid, methanesulfonic acid or lactic acid. In another embodiment, the acid is methanesulfonic acid.
In another embodiment, the pharmaceutical composition further comprises a tonicity agent. Suitable examples of a tonicity agent include amino acids (e.g., alanine and glycine), electrolytes (e.g., sodium chloride and potassium chloride), monosaccharides (e.g. glucose or galactose), disaccharides (e.g. sucrose) and hexahydric alcohols (e.g., mannitol and sorbitol). In another embodiment, the tonicity agent is sodium chloride, glucose, mannitol, or sorbitol in another embodiment, the tonicity agent is a hexahydric alcohol. In another embodiment, the tonicity agent is sorbitol.
SNS-595 is a cytotoxic agent for the treatment of cancer. The types of cancers that can be treated using the inventive methods include but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer (both small cell and non-small cell), lymphoma, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.
hi another aspect of the invention, a method of using SNS-595 to treat a human cancer is provided. The method comprises administering to a patient on the basis of body surface area, a dose of 10 mg/m2-150 mg/m2 of SNS-595. Body surface area calculations can be calculated for example, with the Mosteller formula wherein:
BSA (m2) = square root of [(height (cm) x weight (kg)/3600].
In another embodiment, the dose is 10 mg/m2-100 mg/m2. In another embodiment, the dose is 30 mg/m2-75 mg/m2. in axiother embodiment, the dose is 40 mg/m2-80 mg/m2. In another embodiment, the dose is 50 mg/m -90 mg/m .
In another embodiment the dose is 20 mg/m2-30 mg/m2-. In another embodiment the dose-is 25 mg/m2-35 mg/m2. In another embodiment the dose is 40 mg/m2-50 mg/m2. In another embodiment the dose is 45 mg/m2-55 mg/m2. in another embodiment the dose is 50 mg/m--60

mg/m . In another embodiment the dose is 55 mg/m -65 mg/m . In another embodiment the dose is 60 mg/m -70 mg/m . In another embodiment the dose is 65 mg/m -75 mg/m". In another embodiment the dose is 70 mg/m2-80 mg/m2. In another embodiment the dose is 75 mg/m2-85mg/m". In another embodiment the dose is 80 mg/m2-90 mg/m . In another embodiment the dose is 85 mg/m2-95 mg/m2. In another embodiment the dose is 90 mg/m2-I00 rng/m2.
In another embodiment the dose is 95 mg/m -105 mg/m . In another embodiment the dose is 100 rng/m2-110 mg/m . In another embodiment the dose is 105 mg/m - 115 mg/m2. In another embodiment the dose is 110 mg/m2-120 mg/m . In another embodiment the dose is 115 mg/m2-125 mg/m2. In another embodiment the dose is 120 mg/m2-130 mg/m2. In another

embodiment the dose is 125 mg/m2- 135 mg/m . In another embodiment the dose is 130 mg/m -

140 mg/m 2. In another embodiment the dose is 135 mg/m2 -145 mg/m2 . In another embodiment the dose is 140 mg/m"-150 mg/m2.
The administered dose of SNS-595 can be delivered simultaneously (e.g. a single bolus injection) or over a 24-hour period (e.g., continuous infusion over time or divided bolus doses over time) and is repeated until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. For example, stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more firom the last measurement. See e.g., Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3): 205-216 (2000). Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.
The administered dose of SNS-595 can be expressed in units other than as mg/m . For example, doses can be expressed as mg/kg. One of ordinary skill in the art would readily know how to convert doses from mg/m2 to mg/kg to given either the height or weight of a subject or both (see e.g., http:///www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 10 mg/m2 -150 mg/m2 for a 65 kg human is approximately equal to 0.26 mg/kg-3.95 mg/kg.

In another aspect of the present invention, SNS-595 is administered according to a dosing schedule. In one embodiment, the method comprises:
i) administering a dose of 10 mg/m2-l 50 mg/m2 of SNS-595 to a patient;
ii) waiting a period of at least one day where the subject is not administered any SNS-595;
iii) administering another dose of 10 mg/m2-150 mg/m2 of SNS-595 to the patient; and,
repeating steps ii)-iii) a plurality of times.
For example, if the waiting period were 6 days, then the initial dose of SNS-595 is administered on Day 1 (step i); the waiting period is six days (step ii); and the following dose of SNS-595 is administered on Day 8 (step iii). Other exemplary time periods include 2 days, 3 days, 13 days, 20 days, and 27 days. In another embodiment, the waiting period is at least 2 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 6 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 6 days and steps ii) through iii) are repeated at least five 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) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 27 days and steps ii) through 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 five times.
In another embodiment, the dosing method comprises administering a weekly dose of SNS-595 to a subject In another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every two weeks. In another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every three weeks, hi another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every four weeks.

In another embodiment, the dosing method comprises a cycle wherein the cycle comprises administering a dose of SNS-595 to a subject every week for three weeks followed by a period of at least two weeks where no SNS-595 is administered to said subject and wherein the cycle is repeated a plurality of times. In another embodiment, the period where no SNS-595 is administered is two weeks. In another embodiment, the period where no SNS-595 is administered is three weeks.
In another aspect of the invention, a method of treating a solid tumor is provided. The method comprises;
i) administering a dose of 10 mg/m2-100 mg/m2 of SNS-595 to a patient;
ii) waiting a period of at least six days where the subject is not administered any SNS-595;
iii) administering another dose of 10 mg/m -100 mg/m2 of SNS-595 to the patient; and,
iv) repeating steps ii)-iii) a plurality of times.
In another aspect of the invention, a method of treating a hematologic cancer such as leukemias and lymphomas is provided. The method comprises:
i) ,- administering a dose of 60 mg/m2-l 50 mg/m2 of SNS-595 to a patient;
ii) waiting a period of at least two days where the subject is not administered any SNS-595;
iii) administering another dose of 60 mg/m -150 mg/m2 of SNS-595 to the patient; and,
iv) repeating steps ii)-iii) a plurality of times.
In another aspect of the present invention, a method is provided supportive care to patients being treated with SNS-595. The method comprises:
a) administering to a patient a dose of 10 mg/m -150 mg/m" of SNS-595 and
b) administering a therapeutically effective amount of a supportive care agent.
The supportive care agent is any substance that prevents or manages an adverse effect from SNS-595 treatment and is administered according to the appropriate dosing regimen for that substance. For example, different supportive care agents for treating nausea have different

dosing regimen. While some are administered prophylactically, others are co-administered with SNS-595 while still others are administered after the administration of SNS-595. Illustrative examples of supportive care agents their doses and dosing regimens are found in The Physician's Desk Reference.
In one embodiment, the supportive care agent is an antiemetic. Illustrative examples of antiemetics include but are not limited to phenothiazines, butyrophenones, benzodiazapines, corticosteroids, serotonin antagonists, cannabinoids, and NK) receptor antagonists. Examples of phenothiazine antiemetics include prochlorperazine and trimethobenzamide. An example of a butyrophenone antiemetic is haloperidol. An example of a benzodiazepine antiemetic is lorazepam. An example of a corticosteroid antiemetic is dexamethasone. Examples of a serotonin antagonist antiemetic include ondansetron, gramsetron, and dolasetron. An example of a cannabinoid antiemetic is dronabinol An example of an NKl receptor antagonist is aprepitant
In another embodiment, the antiemetic is prochlorperazine. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is 10 mg. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is an oral dose of 10 mg before the administration of SNS-595. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is an oral dose of 10 mg every four to six hours as needed after the administration of SNS-595.
In another embodiment, the antiemetic is dexamethasone. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is at least 4 mg. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is an oral dose of 4 mg before the administration of SNS-595. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is an oral dose of 8 mg before the administration of SNS-595. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is an intravenous dose of between about 10 mg and about 20 mg before the administration of SNS-595. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is an oral dose of 4 mg every six to twelve hours as needed after the administration of SNS-595.

In another embodiment, the antiemetic is lorazepam. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is 1 mg. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an oral dose of 1 mg before the administration of SNS-595. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an intravenous dose of 1 mg before the administration of SNS-595. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an oral dose of 1 mg every four to six hours as needed after the administration of SNS-595.
In another embodiment the antiemetic is dolasetron. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is 100 mg. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is an oral dose of 100 mg before the administration of SNS-595. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is an intravenous dose of 100 mg before the administration of SNS-595.
In another embodiment the antiemetic is ondansetron. In another embodiment the antiemetic is ondansetron and the therapeutically effective amount is at least 10 mg. In another embodiment, the antiemetic is ondansetron and the therapeutically effective amount is an intravenous dose of 10 mg before the administration of SNS-595. In another embodiment the antiemetic is ondansetron and the therapeutically effective amount is an intravenous dose of 32 mg before the administration of SNS-595.
In another embodiment the antiemetic is granisetron. In another embodiment the antiemetic is granisetron and the therapeutically effective amount is 10 μ ig/kg. In another embodiment the antiemetic is granisetron and the therapeutically effective amount is an intravenous dose of 10 μ g/kg before the administration of SNS-595. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is at least 1 mg. In another embodiment the antiemetic is granisetron and the therapeutically effective amount is an oral dose of 1 mg before the administration of SNS-595. In another embodiment the antiemetic is granisetron and the therapeutically effective amount is an oral dose of 2 mg before the administration of SNS-595.

In another embodiment, the antiemetic is aprepitant. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is at least 80 mg. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is an oral dose of 125 mg before the administration of SNS-595. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is a daily oral dose of 80 mg for at least two days after the administration of SNS-595.
In another embodiment, the supportive care agent is a hematopoietic agent. A hematopoietic agent is a molecule that stimulates hematopoiesis. Illustrative examples of hematopoietic agents include but are not limited to granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin and erythropoiesis stimulating protein, and derivatives thereof. Examples of G-CSF include but are not limited to filgrastim and its derivatives including pegfilgrastim. An example of GM-CSF includes sargramostim. An example of erythropoietin is epoetin alfa. An example of erythropoiesis stimulating protein is darbepoetin alia.
In another embodiment, the hematopoietic agent is G-CSF. In another embodiment, the hematopoietic agent is filgrastim, hi another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is at least 4 μg/kg. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is a daily dose of at least 4 jig/kg for at least 7 days after the administration of SNS-595. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is a daily subcutaneous dose of between about 4 μg/kg and about 8 μg/kg for at least 7 days starting from the third day after the administration of SNS-595. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is a daily subcutaneous dose of between about 4 μg/kg and about 10 μg/kg for at least 14 days starting from the third day after the administration of SNS-595.
In another embodiment, the hematopoietic agent is pegfilgrastim. In another embodiment the hematopoietic agent is pegfilgrastim and the therapeutically effective amount is 6 mg. In another embodiment, the hematopoietic agent is pegfilgrastim and the therapeutically effective amount is a daily subcutaneous dose of 6 mg after the administration of SNS-595. In another embodiment, the hematopoietic agent is pegfilgrastim and the therapeutically effective

amount is 100 μg/kg. In another embodiment, the hematopoietic agent is pegfilgrastrm and the therapeutically effective amount is a daily dose of 100 ug/kg after the administration of SNS-595.
In another embodiment, the hematopoietic agent is GM-CSF. In another embodiment, the hematopoietic agent is sargramostim. In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is 250 μg/m2. In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 μg/m2. In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 μg/m2 as needed starting from the third day after the administration of SNS-595. la another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 μg/m2 as needed starting from the tenth day after the administration of SNS-595.
In another embodiment, the hematopoietic agent is erythropoietin. In another embodiment, the hematopoietic agent is epoetin alfa. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is at least 150 units/kg. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is an intravenous or subcutaneous dose of 150 units/kg three times a week after the administration of SNS-595. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is an intravenous or subcutaneous dose of 300 units/kg three times a week after the administration of SNS-595. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is 40,000 units. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is a weekly dose of 40,000 units after the administration of SNS-595.
In another embodiment, the hematopoietic agent is erythropoiesis stimulating protein. In another embodiment, the hematopoietic agent is darbepoetin alfa. In another embodiment, the - hematopoietic agent is darbepoetin alfa and the therapeutically effective amount is between about 1.5 μg/kg and about 4.5 μg/kg. In another embodiment, the hematopoietic agent is darbepoetin alfa and the therapeutically effective amount is a weekly dose of between about 1.5 μg/kg and about 4.5 μg/kg.

All cited references are incorporated herein by reference.
EXAMPLE 1
Pharmaceutical composition suitable for injection or intravenous infusion
Acidic compositions ( EXAMPLE 2
Pharmacokinetics of SNS-595 in cancer patients
SNS-595 was administered to enrolled patients for up to six cycles. A cycle is defined as a three-week period, with SNS-595 administered on the first day of each cycle (day 0), followed by at least 21 days of observation. SNS-595 was administered to cohorts of at least 3 patients and dose escalation occurred by sequential cohort. Doses of SNS-595 were linear with AUC oo and its pharmacokinetic properties were remarkably consistent among patients in the same cohort. Figure 1 depicts the plasma concentrations of SNS-595 overtime among the various patient cohorts and Table 1 shows the pharmacokinetic parameters derived there from.

What is claimed is:
1. A method for treating cancer comprising administering to a patient a dose of 10 mg/m2-150 mg/m2 of SNS-595.
2. The method of claim 1 wherein the dose is 10 mg/m -100 mg/m2.
3. The method of claim 1 wherein the dose is 30 mg/m2 -75 mg/m2.
4. The method of claim 1 wherein fee dose is 40 mg/m2-80 mg/m2.
5. The method of claim 1 wherein the dose is 50 mg/m2-90 mg/m2.
6. The method of claim 1 wherein the cancer being treated is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.
7. The method of claim 1 wherein the dose is 10 mg/m2-100 mg/m2 and the cancer being treated is a solid tumor.
8. The method of claim 1 wherein the dose is 60 mg/m -150 mg/m and the cancer being treated is a hematologic cancer.
9. The method of claim 1 additionally comprising administering to a patient a therapeutically effective dose of a supportive care agent.
10. The method of claim 9 wherein the supportive care agent is an antiemetic.
11. The method of claim 9 wherein the supportive care agent is a hematopoietic
agent.
12. A method comprising:
i) administering a dose of 10 mg/m 2-150 mg/m2 of SNS-595 to apatient;
ii) waiting a period of at least one day where the subject is not administered any
SNS-595;

iii) administering another dose of 10 mg/m2-150 mg/m2 of SNS-595 to the patient; and, iv) repeating steps ii)-iii) a plurality of times.
13. The method of claim 12 wherein the waiting period is at least 2 days.
14. The method of claim 12 wherein the waiting period is at least 3 days.
15. The method of claim 12 wherein the waiting period is at least 6 days.
16. The method of claim 12 wherein the waiting period is at least 13 days.
17. The method of claim 10 wherein the waiting period is at least 20 days.
18. The method of claim 10 wherein the waiting period is at least 27 days
19. A method comprising administering a weekly dose of SNS-595 to a patient.
20. A method comprising administering a dose of SNS-595 to a patient every three weeks.
21. A method comprising a cycle wherein the cycle comprises administering a dose of SNS-595 to a subject every week for three weeks followed by a period of at least two weeks where no SNS-595 is administered to said subject and wherein the cycle is repeated a plurality of
times.
22. A method for treating cancer comprising administering to a patient a dose of 10 mg/m2 -150 mg/m of SNS-595 and administering a patient a therapeutically effective dose of a hematopoietic agent.
23. The method of claim 22 wherein the hematopoietic agent is G-CSF.
24. The method of claim 22 wherein the hematopoietic agent is GM-CSF.
25. The method of claim 22 wherein the hematopoietic agent is erythropoietin.
26. The method of claim 22 wherein the hematopoietic agent is erythropoiesis stimulating protein.
NEW CLAIMS
27. A use of SNS-595 in the manufacture of a composition for treating cance, wherein the composition is administered to a patient in a dose of 10 mg/ m2-150mg/ m2 of SNS-595.
28. The use of claim 27. wherein the dose is 10 rng/m2-100mg/m2.
29. The use of claim 27. wherein the dose is 30mg/ m2-75mg/ m2.
30. The use of claim 27. wherein the dose is 40mg/ m2-80rng/ m2.
31. The use of claim 27, wherein the dose is 50mg/ m2-90mg/ m2.
32. The use of claim 27, wherein the cancer being treated is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphom, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.
33. The use of claim 27. wherein the dose is 10mg/ m2-l00mg/ m2 and the cancer being treated is a solid tumor.
34. The use of claim 27. wherein the dose is 60 mg/ m2-150mg/ m2 and the cancer beins treated is a hematologic cancer.
35. The use of claim 27 additionally comprising administering to a patient a therapeutically effective dose of a supportive care agent.
36. The use of claim 35. wherein the supportive care agent is an antiemetic.
37. The use of claim 35, wherein the supportive care agent is a hematopoietic agent.
38. The use of SNS-595 in manufacturing a composition for use in a method comprising:
i) administering a dose of 10mg/m2-150 mg/m2 of SNS-595 to a patient:
ii) waiting a period of at least one day where the subject is not administered any
SNS-595;
iii) administering another dose of 10 mg/m2-l 50mg/m2 of SNS-595 to the patient: and
iv) repeating steps ii) -iii) a plurality of times.
39. The use of claim 38. wherein the waiting period is at least 2 days.
40. The use of claim 38. wherein the waiting period is at least 3 days.
41. The use of claim 38, wherein the waiting period is at least 6 days.

42. The use of claim 38. wherein the waiting period is at least 13 days.
43. The use of claim 38. wherein the waiting period is at least 20 days.
44. The use of claim 38. wherein the waiting period is at least 27 days
45. The use of SNS-595 in manufacturing a composition for use in administering a weekly dose of SNS-595 to a patient.
46. The use of SNS-595 in manufacturing a composition for use in administering a dose of SNS-595 to a patient every three weeks.
47. The use of SNS-595 in manufacturing a composition for use in method comprising a cycle, wherein the cycle comprises administering a dose of SNS-595 to a subject every week for three weeks followed by a period of at least two weeks where no SNS-595 is administered to said subject and wherein the cycle is repeated a plurality of times.
48. The use of SNS-595 in manufacturing a composition for use in a method for treating cancer comprising administering to a patient a dose of 1 0mg/m2-150mg/m2 of SNS-595 and administering a patient a therapeutically effective dose of a hematopoietic agent.
49. The use of claim 48. wherein the hematopoietic agent is G-CSF.
50. The use of claim 48. wherein the hematopoietic agent is GK4-CSF.
51. The use of claim 48, wherein the hematopoietic agent is erythropoietin.
52. The use of claim 48. wherein the hematopoietic agent is erythropoiesis stimulating protein.
53. A pharmaceutical composition comprising (+)-l,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methy lam ino)-l -pyrrol id inylj-4-ox.o-l -(2-th iazoly I)-1,8-naphthyridine-3-carboxylic acid and an acid.
54. The pharmaceutical composition of claim 53 further comprising water.
55. The pharmaceutical composition of claim 53, wherein a pH of the composition is
less than 4.
56. The pharmaceutical composition of claim 53, wherein the pH of the composition is between 2.3 to 2.7.
57. The composition of claim 53, wherein the acid is an organic or inorganic acid.
58. The composition of claim 57. wherein the acid is selected from acetic acid, ascorbic acid, benzenesulfonic acid, ethanesulfonic acid, glycolic acid, hydrogen chloride. hydrogen bromide, hydroxyethanesulfonic acid, lactic acid, maleic acid, methanesuifonic acid, proprionic acid, succinic acid, sulfuric acid, trifluoroacetic acid and toluenesulfonic acid.

59. The pharmaceutical composition of claim 53. wherein the acid is methanesuifonic
acid.
60. The pharmaceutical composition of claim 53 further comprising a tonicity agent.
61. The pharmaceutical composition of claim 60. wherein the tonicity agent is
selected from an amino acid, electrohte. monosaccharide, disaccharide and hexahydric alcohol.
62. The pharmaceutical composition of claim 60. wherein the tonicity agent is
sorbitol.
63. The pharmaceutical composition of claim 53, wherein (+)-1,4-dihydro-7-[(3S.4S)-
3-methoxy-4-(methylamino)-l-pyrrolidinyI]-4-oxo-l-(2-thiazolyl)-l ,8-naphthyridine-3-
carboxylic acid is present in an amount 10 mg/mL.
64. The pharmaceutical composition of claim 63. wherein the sorbitol is present in an
amount 4.5%.
65. The pharmaceutical composition of claim 53. wherein the pH of the composition
is 2.5.
66. The pharmaceutical composition of claim 53, wherein the composition comprises
1 00 rng of (-)-1.4-dihydro-7-[(3S.4S}-3-methoxy-4-(methyl,amino)-1 -pyrroiidinyI]-4-oxo-1 -(2-
thiazolyl)-! .8-naphthyridine-3-carhoxylic acid and 450 mg of sorbitol per 10 mL of the
composition.
67. A lyophilized powder comprising (+)-l ,4-dihydro-7-[(3S.4S)-3-methoxy-4-
(methylamino)-] -pyrrolidinyI]-4-oxo-l -(2-thiazolyl)-1.8- naphthyridine-3-carboxylic acid and an
acid.
68. An aqueous pharmaceutical composition comprising 100 mg of (+)-],4-dihydro-
7-[(3S,4S)-3-methoxy-4-(methy lam ino)-l-pyrrol idiny I]- 4-oxo-l -(2-th iazoly I)- 1.8-naphthy rid ine-
3-carboxylic acid and 450 mg of sorbitol per 10 mL of the composition, wherein the composition
has a pH of 2.5 adjusted with methanesuifonic acid.

Documents:

3809-CHENP-2006 AMENDED PAGES OF SPECIFICATION 03-12-2012.pdf

3809-CHENP-2006 AMENDED CLAIMS 03-12-2012.pdf

3809-CHENP-2006 CLAIMS.pdf

3809-CHENP-2006 CORRESPONDENCE OTHERS.pdf

3809-CHENP-2006 EXAMINATION REPORT REPLY RECEIVED 03-12-2012.pdf

3809-CHENP-2006 FORM-1 03-12-2012.pdf

3809-CHENP-2006 FORM-13 17-03-2008.pdf

3809-CHENP-2006 FORM-13.pdf

3809-CHENP-2006 FORM-18.pdf

3809-CHENP-2006 FORM-3 03-12-2012.pdf

3809-CHENP-2006 OTHER PATENT DOCUMENT 03-12-2012.pdf

3809-CHENP-2006 OTHERS 03-12-2012.pdf

3809-CHENP-2006 POWER OF ATTORNEY 03-12-2012.pdf

3809-CHENP-2006 CORRESPONDENCE OTHERS 06-01-2012.pdf

3809-chenp-2006-abstract.pdf

3809-chenp-2006-assignement.pdf

3809-chenp-2006-claims.pdf

3809-chenp-2006-correspondnece-others.pdf

3809-chenp-2006-description(complete).pdf

3809-chenp-2006-drawings.pdf

3809-chenp-2006-form 1.pdf

3809-chenp-2006-form 3.pdf

3809-chenp-2006-form 5.pdf

3809-chenp-2006-pct.pdf

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Patent Number

254943

Indian Patent Application Number

3809/CHENP/2006

PG Journal Number

02/2013

Publication Date

11-Jan-2013

Grant Date

07-Jan-2013

Date of Filing

13-Oct-2006

Name of Patentee

DAINIPPON SUMITOMO PHARMA CO., LTD

Applicant Address

6-8, DOSHO-MACHI 2-CHOME, CHUO-KU, OSAKA-SHI, OSAKA 541-8524, JAPAN

Inventors:

#	Inventor's Name	Inventor's Address
1	SILVERMAN, JEFFREY, A	1416 COLUMBUS AVENUE, BURLINGAME, CA 94010, USA
2	MASARU, HIGAKI	5-51, EBIE 1-CHOME, FUKUSHIMA-KU, OSAKA-SHI, OSAKA 553-0001, JAPAN
3	SATOSHI, NAKAO	5-51, EBIE 1-CHOME, FUKUSHIMA-KU, OSAKA-SHI, OSAKA 553-0001, JAPAN
4	ADELMAN, DANIEL, C	23 WOODLEAF AVENUE, REDWOOD CITY, CA 94061, USA

PCT International Classification Number

A61K 31/44

PCT International Application Number

PCT/US05/08346

PCT International Filing date

2005-03-14

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/553,578	2004-03-15	U.S.A.