Dosage and administration of anti-egfr therapeutics

Abstract

Methods for optimizing a therapeutic response in a patient (e.g., a cancer patient) to an anti-EGFR therapy, and methods for preventing or ameliorating infusion reactions in a patient receiving an anti-EGFR therapy are disclosed.

What is claimed is: 
     
         1 . A method of administering a mixture of two or more monoclonal anti-EGFR antibodies to a human cancer patient,
 the method comprising initially administering the mixture to the patient as a first and a second intravenous infusion during an initial two week treatment cycle, comprising a first week and a second week, wherein:
 i. a first dose of the mixture of anti-EGFR antibodies is administered during the first week at a rate of X mg/hour for a first ½ hour, immediately followed by a rate of 2X mg/hour for a second ½ hour, immediately followed by a rate of 4X mg/hour until all of the first dose has been administered; and 
 ii. a second dose of the mixture of anti-EGFR antibodies is administered during the second week at a rate of X mg/hour for a first ½ hour, immediately followed by a rate of 2X mg/hour for a second ½ hour, immediately followed by a rate of 4X mg/hour for a third ½ hour, immediately followed by a rate of 8X mg/hour until all of the second dose has been administered. 
   
     
     
         2 . The method of  claim 1 , wherein prior to each infusion of the mixture of anti-EGFR antibodies, diphenhyradmine is administered to the patient orally or intravenously at a dose of 25 mg-50 mg. 
     
     
         3 . The method of  claim 1 , wherein prior to each infusion of the mixture of anti-EGFR antibodies, methylprednisolone is administered to the patient intravenously at a dose of 25 mg-125 mg. 
     
     
         4 . The method of  claim 1 , wherein prior to each infusion of anti-EGFR antibodies, acetaminophen is administered to the patient at a dose of 650 mg. 
     
     
         5 . The method of  claim 1 , wherein the mixture of monoclonal anti-EGFR antibodies is administered to a human cancer patient diagnosed with colorectal cancer, head and neck cancer, non-small cell lung cancer, gastric cancer, breast cancer, endometrial cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, brain cancer, liver cancer, pancreatic cancer, or squamous cell carcinoma. 
     
     
         6 . The method of  claim 1 , wherein X is 25. 
     
     
         7 . The method of  claim 1 , wherein the first dose is about 225 mg or is about 3 mg/kg. 
     
     
         8 . The method of  claim 1 , wherein the second dose is about 450 mg or is about 6 mg/kg. 
     
     
         9 . The method of  claim 1 , wherein the mixture of anti-EGFR antibodies consists of anti-EGFR antibodies that specifically bind to two or more different epitopes of the extracellular domain of EGFR. 
     
     
         10 . The method of  claim 1 , wherein the mixture comprises two or more anti-EGFR antibodies selected from the group consisting of:
 i) a first antibody comprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 7, 8 and 9 respectively, and light chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 10, 11 and 12 respectively;   ii) a second antibody comprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 13, 14 and 15 respectively and light chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 16, 17, and 18 respectively; and   iii) a third antibody comprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 19, 20 and 21 respectively, and light chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 22, 23 and 24 respectively.   
     
     
         11 . The method of  claim 10 , wherein the mixture comprises three anti-EGFR antibodies. 
     
     
         12 . The method of  claim 11 , wherein the mixture of three anti-EGFR antibodies is MM-151 and the first antibody, the second antibody, and the third antibody are formulated in a mixture at a molar ratio to each other of 2:2:1, respectively. 
     
     
         13 . The method of  claim 1 , wherein the mixture of monoclonal anti-EGFR antibodies is administered in further combination with liposomal irinotecan. 
     
     
         14 . The method of  claim 1 , wherein, if the patient tolerates the initial cycle, the at least one cycle further comprises at least one subsequent treatment cycle, each subsequent treatment cycle comprising at least one administration of the mixture of anti-EGFR antibodies at a third dose. 
     
     
         15 . The method of  claim 14 , wherein the third dose of the mixture of anti-EGFR antibodies is administered at a rate of 2X mg/hour for a first ½ hour, immediately followed by a rate of 4X mg/hour for a second ½ hour, immediately followed by a rate of 8X mg/hour for a third ½ hour, immediately followed by a rate of 16X mg/hour until all of the third dose has been administered. 
     
     
         16 . The method of  claim 14 , wherein the at least one subsequent treatment cycle has a duration of three weeks or four weeks. 
     
     
         17 . The method of  claim 14 , wherein the third dose of the mixture of anti-EGFR antibodies is 4.5 mg/kg, 6 mg/kg, 7.5 mg/kg, 9 mg/kg, 10 mg/kg, 10.5 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 18 mg/kg, and 20 mg/kg; and is administered weekly, bi-weekly or tri-weekly. 
     
     
         18 . A method of administering a mixture of two or more monoclonal anti-EGFR antibodies to a human cancer patient,
 the method comprising initially administering the mixture to the patient as a first and a second intravenous infusion over a two week cycle as priming doses in sequence as set forth in the following table:   
       
         
           
                 
                 
                 
                 
                 
               
                     
                 
                     
                   Infusion 
                     
                   Mixture 
                   Cumulative 
                 
                     
                   Rate 
                   Infusion Rate 
                   Infused 
                   Mixture 
                 
                   Infusion 
                   Sequence 1   
                   (mg/hr) 
                   (mg) 
                   Infused (mg) 
                 
                     
                 
                     
                 
                 
                 
                 
                 
                 
               
                   1 st  Infusion 
                   1 st  Rate 
                   25 
                   12.5 
                   12.5 
                 
                   (Priming Week 1) 
                   2 nd  Rate 
                   50 
                   25.0 
                   37.5 
                 
                     
                   3 rd  Rate 
                   100 
                   187.5 
                   225.0 
                 
                   2 nd  Infusion 
                   1 st  Rate 
                   25 
                   12.5 
                   12.5 
                 
                   (Priming Week 2) 
                   2 nd  Rate 
                   50 
                   25.0 
                   37.5 
                 
                     
                   3 rd  Rate 
                   100 
                   50.0 
                   87.5 
                 
                     
                   4 th  Rate 
                   200 
                   362.5 
                   450 
                 
                     
                 
                     1 per infusion 
                 
             
                
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein the 1 st  infusion of the mixture is administered during the priming week 1 at the 1 st  rate for a ½ hour, immediately followed by the 2 nd  rate for a second ½ hour, immediately followed by the 3 rd  rate until all of the first dose and 225 mg of mixture has been administered; 
         wherein the 2 nd  infusion of the mixture is administered during priming week 2 at the 1 st  rate for a ½ hour, immediately followed by the 2 nd  rate for the second ½ hour, immediately followed by the 3 rd  rate for a ½ hour, immediately followed by the 4 th  rate until all of the first dose and 450 mg of mixture has been administered; and 
         wherein the mixture of monoclonal IgG1 anti-EGFR antibodies is administered to a human cancer patient diagnosed with colorectal cancer. 
       
     
     
         19 . The method of  claim 18 , wherein prior to each infusion of the mixture of anti-EGFR antibodies, diphenhydramine is administered to the patient orally or intravenously at a dose of 25 mg-50 mg. 
     
     
         20 . The method of  claim 18 , wherein prior to each infusion of the mixture of anti-EGFR antibodies, methylprednisolone is administered to the patient intravenously at a dose of 25 mg-125 mg. 
     
     
         21 . The method of  claim 18 , wherein prior to each infusion of the mixture of anti-EGFR antibodies, acetaminophen is administered to the patient at a dose of 650 mg. 
     
     
         22 . The method of  claim 18 , wherein the method comprises administering the mixture of anti-EGFR antibodies in combination with liposomal irinotecan. 
     
     
         23 . The method of  claim 18 , wherein the mixture comprises two or more anti-EGFR antibodies selected from the group consisting of:
 i) a first monoclonal antibody comprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NO: 7, 8 and 9 respectively, and light chain CDRs 1, 2 and 3 set forth in SEQ ID NO: 10, 11 and 12 respectively;   ii) a second monoclonal antibody comprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NO: 13, 14 and 15 respectively and light chain CDRs 1, 2 and 3 set forth in SEQ ID NO: 16, 17, and 18 respectively; and   iii) a third monoclonal antibody comprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NO: 19, 20 and 21 respectively, and light chain CDRs 1, 2 and 3 set forth in SEQ ID NO: 22, 23 and 24 respectively.   
     
     
         24 . The method of  claim 23 , wherein the mixture comprises three anti-EGFR antibodies. 
     
     
         25 . The method of  claim 24 , wherein the mixture of three monoclonal anti-EGFR antibodies is MM-151 and the first antibody, the second antibody, and the third antibody are formulated in a mixture at a molar ratio to each other of 2:2:1, respectively.