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 an antecedent hematological disorder comprising administering to a mammal having the antecedent hematologic disorder a therapeutically effective amount of an 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. 
     
     
         2 . The method of  claim 1 , wherein the antecedent hematological disorder is a myelodysplastic syndrome. 
     
     
         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 2 , 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 2 , 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, anti-cancer agent, corticosteroid. 
     
     
         9 . The method of  claim 8 , wherein the anti-cancer agent is an alkylating agent, an anti-neoplastic antibiotic, an anti-metabolite, a platinum coordination complex, a topoisomerase II inhibitor, or radiation. 
     
     
         10 . The method of  claim 8 , wherein the anti-cancer 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 anti-cancer 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 . The method of  claim 11 , wherein the amount of cytarabine is about 400 mg/m 2 /day. 
     
     
         14 . The method of  claim 11 , wherein the amount of cytarabine is about 10-50 mg/m 2 /day. 
     
     
         15 . The method of  claim 11 , wherein the amount of cytarabine is about 20 mg/m 2 /day. 
     
     
         16 . The method of  claim 11 , wherein the amount of cytarabine is about 10 mg/m 2  twice per day. 
     
     
         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 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 administered is from about 1 to about 150 mg/m 2 . 
     
     
         19 . The method of  claim 1 , wherein the amount of 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 administered is from about 10 to about 120 mg/m 2 . 
     
     
         20 . The method of  claim 1 , wherein the 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 is administered once a week. 
     
     
         21 . The method of  claim 20 , wherein the 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 is administered at a dose of from about 10 to about 90 mg/m 2 . 
     
     
         22 . The method of  claim 21 , wherein the 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 is administered once a week for three weeks. 
     
     
         23 . The method of  claim 1 , wherein the amount of 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 administered is from about 40 to about 80 mg/m 2  per week. 
     
     
         24 . The method of  claim 1 , wherein the 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 is administered as an IV injection. 
     
     
         25 . The method of  claim 1 , wherein the 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 is administered twice per week. 
     
     
         26 . The method of  claim 25 , wherein the 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 administered twice per week is at a dose of from about 10 to about 40 mg/m 2 . 
     
     
         27 . The method of  claim 25 , wherein the 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 is administered twice per week for two weeks. 
     
     
         28 . The method any  claim 1 , wherein the 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 is administered from about 5 to about 60 mg/m 2  twice per week, for 2 weeks. 
     
     
         29 . The method of  claim 11 , wherein the 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 is administered intravenously twice per week, and cytarabine is intravenously administered continuously over a treatment cycle of 5 days. 
     
     
         30 . The method of  claim 29 , wherein cytarabine is administered at about 400 mg/m 2 /day. 
     
     
         31 . The method of  claim 29 , wherein the 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 is administered on day 1 and day 4 of said treatment cycle of 5 days. 
     
     
         32 . The method of  claim 29 , wherein the treatment cycle is repeated at least once. 
     
     
         33 . The method of  claim 29 , wherein the treatment cycle is repeated at least two times. 
     
     
         34 . The method of  claim 29 , wherein the treatment cycle is repeated at least three times. 
     
     
         35 . The method of  claim 11 , wherein the 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 is administered 8 to 16 hours after the start of at least one cytarabine administration. 
     
     
         36 . The method of  claim 11 , wherein the 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 is administered within 24 hours before or after the start of at least one cytarabine administration. 
     
     
         37 . The method of  claim 11 , wherein cytarabine is administered immediately after administration of the 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. 
     
     
         38 . The method of  claim 1 , wherein the mammal is a human.