Combined treatment with keratinocyte growth factor and epidermal growth factor inhibitor

Abstract

The present invention relates to compositions and methods for treating the epithelial toxicity caused by administering to a human cancer patient an epidermal growth factor receptor (EGFR) inhibitor. The pharmaceutical composition preferably comprises an EGFR inhibitor and a keratinocyte growth factor (KGF) in a pharmaceutically-acceptable carrier. The method of treatment comprises co-administering to the patient a therapeutically effective amount of KGF with the EGFR inhibitor.

1 . A pharmaceutical composition comprising an epidermal growth factor receptor (EGFR) inhibitor and a keratinocyte growth factor (KGF) in a pharmaceutically acceptable carrier. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the EGFR inhibitor is a small organic molecule, an antibody or an antibody fragment that binds specifically to the EGFR. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the EGFR inhibitor is selected from the group consisting of quinazoline EGFR inhibitors, pyrido-pyrimidine EGFR inhibitors, pyrimido-pyrimidine EGFR inhibitors, pyrrolo-pyrimidine EGFR inhibitors, pyrazolopyrimidine EGFR inhibitors, phenylamino-pyrimidine EGFR inhibitors, oxindole EGFR inhibitors, indolocarbazole EGFR inhibitors, phthalazine EGFR inhibitors, isoflavone EGFR inhibitors, quinalone EGFR inhibitors, and tyrphostin EGFR inhibitors. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the EGFR inhibitor is selected from the group consisting of [6,7-bis(2-methoxyethoxy)-4-quinozolin-4-yl]-(3-ethynylphenyl)amine, ZD1839 (Iressa) and PC183805. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the EGFR inhibitor is a monoclonal antibody or an antibody fragment. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the EGFR inhibitor is monoclonal antibody Mab E7.6.3, or Mab C225, or an antibody or antibody fragment having the binding specificity thereof. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the KGF is human KGF-1, or an analog thereof having at least partial human KGF-1 activity. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the KGF is human KGF-2, or an analog thereof having at least partial human KGF-2 activity. 
     
     
         9 . A method of treating the epithelial toxicity resulting from administration to a patient of an EGFR inhibitor, comprising co-administering to the patient a therapeutically effective amount of KGF with the EGFR inhibitor. 
     
     
         10 . The method of  claim 9 , wherein the patient is a human that is being treated for cancer. 
     
     
         11 . The method of  claim 9 , wherein the epithelial toxicity is a skin toxicity. 
     
     
         12 . The method of  claim 11 , wherein the skin toxicity is manifested as a rash. 
     
     
         13 . The method of  claim 9 , wherein the epithelial toxicity is manifested as corneal thinning. 
     
     
         14 . The method of  claim 9 , wherein the epithelial toxicity is manifested as diarrhea. 
     
     
         15 . The method of  claim 9 , wherein the EGFR inhibitor and KGF are co-administered to the patient in the same formulation. 
     
     
         16 . The method of  claim 9 , wherein the EGFR inhibitor and KGF are co-administered to the patient in different formulations. 
     
     
         17 . The method of  claim 9 , wherein the EGFR inhibitor and KGF are co-administered to the patient by the same route. 
     
     
         18 . The method of  claim 9 , wherein the EGFR inhibitor and KGF are co-administered to the patient by different routes. 
     
     
         19 . The method of  claim 9 , wherein the EGFR inhibitor is administered to the patient by parenteral or oral administration. 
     
     
         20 . The method of  claim 9 , wherein KGF is administered to the patient by parenteral or topical administration. 
     
     
         21 . The method of  claim 9 , wherein the EGFR inhibitor is a small organic molecule, an antibody or an antibody fragment that binds specifically to the EGFR. 
     
     
         22 . The method of  claim 9 , wherein the EGFR inhibitor is selected from the group consisting of quinazoline EGFR inhibitors, pyrido-pyrimidine EGFR inhibitors, pyrimidopyrimidine EGFR inhibitors, pyrrolo-pyrimidine EGFR inhibitors, pyrazolo-pyrimidine EGFR inhibitors, phenylamino-pyrimidine EGFR inhibitors, oxindole EGFR inhibitors, indolocarbazole EGFR inhibitors, phthalazine EGFR inhibitors, isoflavone EGFR inhibitors, quinalone EGFR inhibitors, and tyrphostin EGFR inhibitors. 
     
     
         23 . The method of  claim 9 , wherein the EGFR inhibitor is selected from the group consisting of [6,7-bis(2-methoxyethoxy)-4-quinozolin-4-yl]-(3-ethynylphenyl)amine, ZD1839 (Iressa) and PC183805. 
     
     
         24 . The method of  claim 9 , wherein the EGFR inhibitor is a monoclonal antibody or an antibody fragment. 
     
     
         25 . The method of  claim 9 , wherein the KGF is human KGF-1, or an analog thereof having at least partial human KGF-1 activity. 
     
     
         26 . The method of  claim 9 , wherein the KGF is human KGF-2, or an analog thereof having at least partial human KGF-2 activity. 
     
     
         27 . A method of preparing a pharmaceutical composition useful for treating the epithelial toxicity resulting from administration to a patient of an EGFR inhibitor, comprising combining a KGF with the EGFR inhibitor. 
     
     
         28 . The method of  claim 27 , further comprising combining a pharmaceutically acceptable carrier with the KGF and EGFR inhibitor. 
     
     
         29 . A kit comprising a container comprising an EGFR inhibitor and KGF. 
     
     
         30 . The kit of  claim 29 , further comprising a sterile diluent. 
     
     
         31 . The kit of  claim 29 , further comprising a package insert comprising printed instructions directing the use of a combined treatment of the KGF and EGFR inhibitor to a patient as a method for treating the epithelial toxicity otherwise resulting from administration to the patient of the EGFR inhibitor alone.