Combination comprising cndac (2'-cyano-2'-deoxy-n4-palmitoyl-1-beta-d-arabinofuranosyl-cytosine) and a cytotoxic agent

Abstract

A first aspect of the invention relates to a combination comprising 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, and a cytotoxic agent selected from: (a) a HDAC inhibitor; and (b) a topoisomerase inhibitor selected from etoposide, topotecan and SN-38, or a prodrug thereof. A second aspect relates to a pharmaceutical product comprising (i) 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, and (ii) a cytotoxic agent selected from: (a) a HDAC inhibitor; and (b) a topoisomerase inhibitor selected from etoposide, topotecan and SN-38, or a prodrug thereof, as a combined preparation for simultaneous, sequential or separate use in therapy. A third aspect relates to a method of treating a proliferative disorder, said method comprising simultaneously, separately or sequentially administering to a subject 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, and a cytotoxic agent selected from: (a) a HDAC inhibitor; and (b) a topoisomerase inhibitor selected from etoposide, topotecan and SN-38, or a prodrug thereof. A fourth aspect of the invention relates to the use of a subject 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cutaneous T-cell lymphoma (CTCL).

1 . A combination comprising 2-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite or pharmaceutically acceptable salt thereof, and a cytotoxic agent, wherein the cytotoxic agent is either selected an HDAC inhibitor or a topoisomerase inhibitor selected from the group consisting of etoposide, topotecan, irinotecan, SN-38, and a prodrug thereof. 
     
     
         2 - 8 . (canceled) 
     
     
         9 . A combination according to  claim 1  wherein the topoisomerase inhibitor is SN-38 or a prodrug thereof. 
     
     
         10 . (canceled) 
     
     
         11 . A combination according to  claim 9  wherein the prodrug of SN-38 is inrinotecan. 
     
     
         12 . A combination according to  claim 1  wherein the topisomerase inhibitor is etoposide or toptecan. 
     
     
         13 . The combination according to  claim 1  wherein the metabolite of 2′-cyano-2′-deoxy-N-palmitoyl-1-β-D-arabinofuranosyl-cytosine is 1-(2-C-cyano-2-deoxy-β-D-arabino-pentafuranosyl)-cytosine (CNDAC). 
     
     
         14 . A combination according to  claim 1  further comprising a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         15 . A pharmaceutical product comprising (i) 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite or pharmaceutically acceptable salt thereof, and (ii) a cytotoxic agent, wherein the cytotoxic agent is either an HDAC inhibitor or a topoisomerase inhibitor selected from the group consisting of etoposide, topotecan, irinotecan, SN-38, and a prodrug thereof. 
     
     
         16 . A pharmaceutical product according to  claim 15  wherein the 2′-cyano-2′-deoxy-N-palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite or pharmaceutically acceptable salt thereof, and the cytotoxic agent are formulated for simultaneous administration. 
     
     
         17 . A pharmaceutical product according to  claim 15  wherein the 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite or pharmaceutically acceptable salt thereof, and the cytotoxic agent are formulated for separate or sequential administration. 
     
     
         18 - 23 . (canceled) 
     
     
         24 . A pharmaceutical product according to  claim 15  wherein the topoisomerase inhibitor is SN-38, or a prodrug thereof. 
     
     
         25 . A pharmaceutical product according to  claim 24  wherein the prodrug of SN-38 is irinotecan. 
     
     
         26 . A pharmaceutical product according to  claim 15  wherein the topoisomerase inhibitor is etoposide or toptecan. 
     
     
         27 . A pharmaceutical product according to  claim 15  wherein the metabolite of 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine is 1-(2-C-cyano-2-deoxy-β-D-arabino-pentafuranosyl)-cytosine. 
     
     
         28 . A pharmaceutical product according to  claim 15  further comprising a pharmaceutical carrier, diluent or excipient. 
     
     
         29 - 36 . (canceled) 
     
     
         37 . A method of treating a proliferative disorder, said method comprising simultaneously, separately or sequentially administering to a subject 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite or pharmaceutically acceptable salt thereof, and a cytotoxic agent, wherein the cytotoxic agent is either an HDAC inhibitor or a topoisomerase inhibitor selected from the group consisting of etoposide, topotecan, and SN-38, and a prodrug thereof. 
     
     
         38 . A method according to  claim 37  wherein the 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or metabolite, or pharmaceutically acceptable salt thereof, and the cytotoxic agent are each administered in a therapeutically effective amount with respect to the individual components. 
     
     
         39 . A method according to  claim 37  wherein the 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or metabolite or pharmaceutically acceptable salt thereof, and the cytotoxic agent are each administered in a sub-therapeutically effective amount with respect to the individual components. 
     
     
         40 . A method according to  claim 37  wherein the 2′-cyano-2′-deoxy-N4-palmitoyl-1-β-D-arabinofuranosyl-cytosine, or metabolite or pharmaceutically acceptable salt thereof, and the cytotoxic agent are administered simultaneously. 
     
     
         41 . A method according to  claim 37  wherein the 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or metabolite or pharmaceutically acceptable salt thereof, and the cytotoxic agent are administered sequentially or separately. 
     
     
         42 . A method according to  claim 41  wherein the 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or metabolite or pharmaceutically acceptable salt thereof, and the cytotoxic agent is administered sequentially or separately prior to the cytotoxic agent. 
     
     
         43 . A method according to  claim 41  wherein the cytotoxic agent is administered sequentially or separately prior to the 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or metabolite or pharmaceutically acceptable salt thereof. 
     
     
         44 . A method  claim 37  wherein the metabolite of 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine is 1-(2-C-cyano-2-deoxy-β-D-arabino-pentafuranosyl)-cytosine. 
     
     
         45 . A method  claim 37 , wherein the proliferative disorder is cancer or lymphoma. 
     
     
         46 . A method according to  claim 45 , wherein the cancer or lymphoma is selected from the group consisting of non-Hodgkin's lymphoma, cutaneous T-cell lymphoma (CTCL), lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), leukemia and acute myelogenous leukemia (AML). 
     
     
         47 - 66 . (canceled) 
     
     
         67 . A kit of parts comprising:
 (i) 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or pharmaceutically acceptable salt thereof, optionally admixed with a pharmaceutically acceptable diluent, excipient or carrier; and   (ii) a cytotoxic agent selected from: (a) a HDAC inhibitor; and (b) a topoisomnerase inhibitor selected from etoposide, topotecan and SN-38, or a prodrug thereof, optionally admixed with a pharmaceutically acceptable diluent, excipient or carrier.   
     
     
         68 . (canceled) 
     
     
         69 . A method of treating cutaneous T-cell lymphoma (CTCL) in a subject, said method comprising administering to said subject a therapeutically effective amount of 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         70 . The method according to  claim 69  wherein the 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof is administered in combination with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         71 . The method according to  claim 69  wherein the 2′-cyano-2′-deoxy-N 4 -palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof is administered in combination with one or more other antiproliferative agents. 
     
     
         72 - 73 . (canceled)