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 treating a cancer in a human patient, the method comprising administering an oligoclonal mixture of anti-EGFR antibodies to the patient, wherein the method comprises intravenously administering the oligoclonal mixture of anti-EGFR antibodies in at least one treatment cycle, the at least one cycle comprising:
 an initial two week treatment cycle consisting of a first week and a second week, wherein a first dose of the oligoclonal 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 a second dose, that is greater than or equal to the first dose, is administered during the second week;   wherein administration, at each rate subsequent to the first ½ hour, is optionally one or more of: delayed, altered or not carried out if the patient exhibits an adverse reaction to the administration at the preceding rate.   
     
     
         2 . The method of  claim 1 , wherein the patient exhibits an adverse reaction to the administration at the preceding rate and the alteration comprises an interruption of administration, and:
 i) the patient is treated for symptoms of the adverse reaction at the discretion of an attending clinician, and   ii) following treatment of the symptoms, the administration is resumed at a rate lower than or equal to the rate at which the administration was interrupted.   
     
     
         3 . The method of  claim 2 , wherein, in ii) the administration is resumed at half the rate at which the administration was interrupted. 
     
     
         4 . The method of any of  claims 1 - 3 , wherein the second dose is administered 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;
 wherein administration at each rate of the second dose is optionally either delayed or not carried out if the patient exhibits an adverse reaction to the administration at the preceding rate or of the preceding dose. 
 
     
     
         5 . The method of  claim 4 , 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 oligoclonal mixture of anti-EGFR antibodies at a third dose. 
     
     
         6 . The method of  claim 5 , wherein the third dose is greater than or equal to the second dose and is greater than the first dose. 
     
     
         7 . The method of  claim 6 , wherein the third dose of the oligoclonal 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;
 wherein administration at each rate of the third dose is optionally either delayed or not carried out if the patient exhibits an adverse reaction to the administration at the preceding rate or of the preceding dose. 
 
     
     
         8 . The method of  claim 7 , wherein X is 25. 
     
     
         9 . The method of  claim 1 , wherein the first dose is about 225 mg or is about 3 mg/kg. 
     
     
         10 . The method of  claim 1 , wherein the second dose is about 450 mg or is about 6 mg/kg. 
     
     
         11 . The method of  claim 5 , wherein the at least one subsequent treatment cycle has a duration of three weeks or four weeks. 
     
     
         12 . The method of  claim 11 , wherein the at least one subsequent treatment cycle has a duration of four weeks, and the third dose is administered on day 1 of each week of the four week treatment cycle. 
     
     
         13 . The method of  claim 11 , wherein the at least one subsequent treatment cycle has a duration of four weeks, and the third dose is administered during the first week and the third week of each four week cycle. 
     
     
         14 . The method of  claim 11 , wherein the at least one subsequent treatment cycle has a duration of three weeks, and the third dose of the oligoclonal mixture of anti-EGFR antibodies is administered during week 1 of each three week cycle. 
     
     
         15 . The method of  claim 1 , wherein the oligoclonal 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. 
     
     
         16 . The method of  claim 15 , wherein the two or more different epitopes is three different epitopes. 
     
     
         17 . The method of  claim 16 , wherein the oligoclonal mixture of anti-EGFR antibodies that specifically bind to three different epitopes of the extracellular domain of EGFR is MM-151bio, optionally MM-151. 
     
     
         18 . The method of  claim 17 , wherein the oligoclonal mixture of anti-EGFR antibodies comprises 3 anti-EGFR antibodies, wherein the 3 anti-EGFR antibodies comprise a first antibody with a heavy chain comprising SEQ ID NO:1 and a light chain comprising SEQ ID NO:2; a second antibody with a heavy chain comprising SEQ ID NO:3 and a light chain comprising SEQ ID NO:4; and a third antibody with a heavy chain comprising SEQ ID NO:5 and a light chain comprising SEQ ID NO:6. 
     
     
         19 . The method of  claim 18 , wherein the third dose of the oligoclonal 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. 
     
     
         20 . The method of  claim 17 , further comprising co-administration of at least one dose of a topoisomerase inhibitor during the initial two week treatment cycle, optionally 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 oligoclonal mixture of anti-EGFR antibodies at a third dose. 
     
     
         21 . The method of  claim 20 , wherein the topoisomerase inhibitor is co-administered during the initial two week treatment cycle, and during that cycle is co-administered prior to administration of the oligoclonal mixture of anti-EGFR antibodies. 
     
     
         22 . The method of  claim 21 , wherein the topoisomerase inhibitor is administered during the at least one subsequent treatment cycle, and during each subsequent cycle is coadministered prior to administration of the oligoclonal mixture of anti-EGFR antibodies. 
     
     
         23 . The method of  claim 20 , wherein the topoisomerase inhibitor is a topoisomerase I inhibitor. 
     
     
         24 . The method of  claim 23 , wherein the topoisomerase I inhibitor is a camptothecin. 
     
     
         25 . The method of  claim 24 , wherein the camptothecin is irinotecan HCl or liposomal irinotecan, optionally liposomal irinotecan sucrosofate. 
     
     
         26 . The method of  claim 20 , wherein each cycle of the at least one subsequent treatment cycle is a four week treatment cycle and the third dose of the oligoclonal mixture of anti-EGFR antibodies and the topoisomerase inhibitor are each administered during day one of week one and day one of week three of the four week treatment cycle, optionally wherein, in each cycle of co-administration, the topoisomerase inhibitor is administered prior to administration of the oligoclonal mixture of anti-EGFR antibodies. 
     
     
         27 . The method of  claim 20 , wherein each cycle of the at least one subsequent treatment cycle is a four week treatment cycle and the topoisomerase inhibitor is administered on day one of week one of each four week treatment cycle and the third dose of the oligoclonal mixture of anti-EGFR antibodies is administered weekly. 
     
     
         28 . The method of  claim 27 , wherein, in each cycle of co-administration, the topoisomerase inhibitor is administered prior to administration of the oligoclonal mixture of anti-EGFR antibodies. 
     
     
         29 . A method of treating a cancer in a human patient, the method comprising one or more administrations by infusion of an oligoclonal mixture of anti-EGFR antibodies to the patient, wherein, prior to each administration of the oligoclonal mixture of anti-EGFR antibodies, a pretreatment comprising an effective amount of:
 1) drug 1: a histamine H1 blocker,   
       and an effective amount of one, or of each of both, of:
 2) drug 2: an anti-inflammatory steroid, and 
 3) drug 3: acetaminophen, 
 
       is administered to the patient. 
     
     
         30 . The method of  claim 29 , wherein the one or both of 2) and 3) are both of 2) and 3) 
     
     
         31 . The method of  claim 29 , wherein the effective amount of each of 1) and one or both of 2) and 3) are all administered to the patient 30-60 minutes prior to the infusion of the oligoclonal mixture of anti-EGFR antibodies. 
     
     
         32 . The method of  claim 29 , wherein 2) is dexamethasone or methylprednisolone. 
     
     
         33 . The method of  claim 32 , wherein the dexamethasone is administered to the patient at a dose of 5, 10, 15, 20 or 25 mg, or the methylprednisolone is administered to the patient at a dose of 25, 50, 75, 100, or 125 mg. 
     
     
         34 . The method of  claim 33 , wherein 2) is methylprednisolone. 
     
     
         35 . The method of  claim 29 , wherein 1) is diphenhydramine. 
     
     
         36 . The method of  claim 35 , wherein the diphenhydramine is administered at a dose of 25 mg to 50 mg. 
     
     
         37 . The method of  claim 36 , wherein the 25 mg to 50 mg is 25 mg or 50 mg. 
     
     
         38 . The method of any one of  claims 29  to  37 , wherein, if the patient develops an infusion reaction in response to an infusion of the oligoclonal mixture of anti-EGFR antibodies, an effective amount of one or both of 1) and 2) is re-administered when the infusion reaction is observed. 
     
     
         39 . The method of any one of  claims 1 - 28 , wherein the treatment of the patient results in a response classified as PR or CR. 
     
     
         40 . The method of any one of  claims 1 - 28 , wherein the treatment of the patient results in a response classified as SD. 
     
     
         41 . The method of  claim 17 , wherein the oligoclonal mixture of anti-EGFR antibodies comprises 3 anti-EGFR antibodies, wherein the 3 anti-EGFR antibodies comprise:
 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.   
     
     
         42 . The method of  claim 18  or  41 , wherein the antibodies are IgG antibodies, optionally IgG1 antibodies. 
     
     
         43 . The method of  claim 41 , wherein the antibodies bind the extracellular domain of EGFR.