Pharmaceutical composition containing a hypomethylating agent and a histone deacetylase inhibitor

Abstract

A pharmaceutical composition for induction therapy which has a hypomethylating agent and a histone deacetylase inhibitor (“HDAC inhibitor”); wherein the hypomethylating agent is a DNA and histone methylation inhibitor such as cladribine and the HDAC inhibitor is, for example, cntinostat, panobinostat, vorinostat, and/or romedepsin; further wherein the hypomethylating agent and the HDAC inhibitor are combined in formulations for various administrations including e.g., a continuous delivery system such as a transdermal patch of at least one reservoir or a plurality of reservoirs, oral, a fixed-dose oral combination, intravenous, and combinations thereof. This pharmaceutical composition for induction therapy is used with a monoclonal antibody in the treatment of various cancers, sarcomas, and other malignancies.

What is claimed is: 
     
         1 . A transdermal composition for induction therapy used with a monoclonal antibody treatment, the composition comprising therapeutically effective amounts of
 a DNA and histone hypomethylating agent; and   a histone deacetylase inhibitor (“HDACi”).   
     
     
         2 . The composition of  claim 1 , wherein the hypomethylating agent is cladribine. 
     
     
         3 . The composition of  claim 2 , wherein the HDACi comprises romidepsin, entinostat, vorinostat, valproic acid, belinostat, panobinostat, or a combination thereof. 
     
     
         4 . The composition of  claim 2 , wherein the HDACi is entinostat. 
     
     
         5 . The composition of  claim 4 , wherein the composition is prepared for administration to a patient via a transdermal patch. 
     
     
         6 . The composition of  claim 2 , wherein the cladribine comprises about 20-100 mg/m 2 . 
     
     
         7 . The composition of  claim 3 , wherein the HDACi comprises about 40-80 mg/m 2 . 
     
     
         8 . The composition of  claim 2 , where in the cladribine comprises about 5-15 mg/m 2 . 
     
     
         9 . The composition of  claim 9 , wherein the HDACi comprises about 10-20 mg/m 2 . 
     
     
         10 . The composition of  claim 1 , wherein the composition comprises molecules wherein the log K ow  values are between 1-3. 
     
     
         11 . A transdermal patch for induction therapy used with a monoclonal antibody treatment, the patch comprising:
 a first reservoir for containing a first component;   a first microporous membrane in fluid communication with the first reservoir, the first membrane having a first porosity;   a second reservoir for containing a second component;   a second microporous membrane in fluid communication with the first reservoir, the second membrane having a second porosity;   wherein the first component comprises a DNA and histone hypomethylating agent in a first transdermal composition and the second component comprises an HDACi in a second transdermal composition; and   wherein the first porosity and the first transdermal composition are selected to transfer an effective amount of the DNA and histone hypomethylating agent across the first membrane over a first desired period of time, and the second porosity and the second transdermal composition are selected to transfer an effective amount of the HDACi across the second membrane over a second desired period of time.   
     
     
         12 . The transdermal patch of  claim 11 , wherein the first porosity and the second porosity are substantially the same. 
     
     
         13 . The transdermal patch of  claim 11 , wherein the first desired period of time and the second desired period of time are substantially the same. 
     
     
         14 . . The transdermal patch of  claim 11 , further comprising an impermeable membrane that separates the first reservoir from the second reservoir. 
     
     
         15 . The transdermal patch of  claim 11 , wherein the first and second microporous membranes define a plurality of holes having a diameter of about 0.1 to about 10 micrometers, to form the first and second porosities. 
     
     
         16 . The transdermal patch of  claim 11 , wherein the DNA and histone hypomethylating agent comprises about 5-15 mg/m 2  of cladribine. 
     
     
         17 . The transdermal patch of  claim 11 , wherein the HDACi comprises about 10-20 mg/m 2 . 
     
     
         18 . The transdermal patch of  claim 11 , wherein the HDACi is entinostat and comprises about 10-20 mg/m 2 . 
     
     
         19 . The transdermal patch of  claim 11 , wherein the DNA and histone hypomethylating agent comprises about 20-100 mg/m 2  of cladribine. 
     
     
         20 . The transdermal patch of  claim 11 , wherein the HDACi comprises about 40-80 mg/m 2 . 
     
     
         21 . The transdermal patch of  claim 11 , wherein the HDACi is entinostat and comprises about 40-80 mg/m 2 . 
     
     
         22 . A method of induction therapy used with a monoclonal antibody in a treatment in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a DNA and histone hypomethylating agent and an HDACi. 
     
     
         23 . The method of  claim 22 , wherein the hypomethylating agent and the HDACi are administered via a transdermal patch. 
     
     
         24 . The method of  claim 22 , wherein the hypomethylating agent is administered orally, and the HDACi is administered via a transdermal patch. 
     
     
         25 . The method of  claim 24 , wherein the hypomethylating agent is cladribine. 
     
     
         26 . The method of  claim 25 , wherein the HDACi comprises romidepsin, entinostat, vorinostat, valproic acid, belinostat, panobinostat or a combination thereof. 
     
     
         27 . The method of  claim 26 , wherein the cladribine is administered in an amount of about 5-20 mg/m 2 . 
     
     
         28 . The method of  claim 27 , wherein the HDACi is administered in an amount of about 10-80 mg/m 2 . 
     
     
         29 . The method of  claim 23 , wherein the cladribine is administered in an amount of about 5-100 mg/m 2  and the HDACi is administered in an amount of about 10-80 mg/m 2 . 
     
     
         30 . The method of  claim 22 , wherein the hypomethylating agent is administered via a transdermal patch and the HDACi is administered orally. 
     
     
         31 . The method of  claim 30 , wherein the hypomethylating agent is cladribine administered in an amount of about 5-100 mg/m 2  and the HDACi is entinostat administered in an amount of about 5-10 mg.