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

Abstract

Methods of treating, preventing or managing antecedent hematologic disorders, such as myelodysplastic syndrome, including chronic myelomonocytic leukemia are disclosed. The methods encompass the administration of SNS-595. Also provided are methods of treatment using this compound with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy. In certain embodiments, the method of treatment comprise administering SNS-595 in combination with cytarabine. Pharmaceutical compositions and single unit dosage forms suitable for use in the methods are also disclosed.

1 . A method of treating a myelodysplastic syndrome comprising administering to a mammal in need thereof a therapeutically effective amount of (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the myelodysplastic syndrome is characterized by ineffective blood cell production, progressive cytopenia, risk of progression to acute leukemia or cellular marrow with impaired morphology. 
     
     
         4 . The method of  claim 1 , wherein the myelodysplastic syndrome is selected from group consisting of refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. 
     
     
         5 . The method of  claim 1 , wherein the myelodysplastic syndrome is chronic myelomonocytic leukemia. 
     
     
         6 . The method of  claim 5 , wherein the chronic myelomonocytic leukemia is relapsed, refractory, or resistant to conventional therapy. 
     
     
         7 . The method of  claim 1 , further comprising administering a therapeutically effective amount of a second active agent. 
     
     
         8 . The method of  claim 7 , wherein the second active agent is a therapeutic antibody that specifically binds to a cancer antigen, hematopoietic growth factor, cytokine, anti-cancer agent, antibiotic, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, corticosteroid, or a pharmacologically active mutant or derivative thereof. 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 7 , wherein the second active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, premetrexed, methotrexate, cytarabine, 5-fluorouracil, wortmannin, geldanamycin, gemcitabine, or a combination thereof. 
     
     
         11 . The method of  claim 10 , wherein the second active agent is cytarabine. 
     
     
         12 . The method of  claim 11 , wherein the amount of cytarabine is about 200 to about 400 mg/m 2 /day. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 11 , wherein the amount of cytarabine is about 10-50 mg/m 2 /day. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 11 , wherein the amount of cytarabine is administered subcutaneously for 10 days. 
     
     
         18 . The method of  claim 1 , wherein the amount of (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid administered is from about 1 to about 150 mg/m 2 . 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 18 , wherein (+) 1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is administered at a dose of from about 10 to about 90 mg/m 2 . 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 1 , wherein (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is administered as an IV injection. 
     
     
         25 - 37 . (canceled) 
     
     
         38 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         39 . The method of  claim 38 , wherein the human has been previously treated with azacytidine or decitabine. 
     
     
         40 . The method of  claim 38 , wherein the human has been previously treated with azacytidine. 
     
     
         41 . The method of  claim 38 , wherein the human has been previously treated with decitabine. 
     
     
         42 . The method of  claim 7 , wherein the second agent is decitabine.