Method of treating cancer

Abstract

Methods are provided of treating a human for cancer comprising administering at least one dose of lapatinib, or a pharmaceutically acceptable salt or composition thereof, to a patient, wherein said patient does not have one or more allelic polymorphisms selected from the group of: HLA-DQA1*0201, HLA-DQB1*0202, and HLA-DRB1*0701. Patients may also be free of genotypes in TNXB; rs12153855 and/or rs17207923.

1 . A method of treating a human for cancer comprising administering at least one dose of lapatinib, or a pharmaceutically acceptable salt or composition thereof, to a said human, wherein said human does not have one or more allelic polymorphisms selected from the group of: HLA-DQA1*0201, HLA-DQB1*0202, and/or HLA-DRB1*0701. 
     
     
         2 . The method of  claim 1 , wherein said human is suffering from breast cancer. 
     
     
         3 . The method according to  claim 1 , wherein said human is free of at least two polymorphisms selected from the group of: HLA-DRB1*0701, HLA-DQA1*0201, and/or HLA-DQB1*0202. 
     
     
         4 . The method according to  claim 1 , wherein said human is also free of the polymorphism in HLA-B*4403. 
     
     
         5 . The method according to  claim 1 , wherein said human is also free of a polymorphism selected from rs12153855 and rs17207923 that reside in the gene TNXB. 
     
     
         6 . The method according to  claim 1 , wherein said human is also free of the Gilbert's syndrome variant UGT1A1*28. 
     
     
         7 . The method according to  claim 1 , wherein lapatinib, or a pharmaceutically acceptable salt or composition thereof, is administered to said human as monotherapy. 
     
     
         8 . The method according to  claim 1 , wherein said lapatinib, or a pharmaceutically acceptable salt or composition thereof, is co-administered with at least one other anti-cancer agent. 
     
     
         9 . The method of  claim 8 , wherein said at least one other anti-cancer agent is selected from the group of: trastuzumab, capecitabine, paclitaxel, carboplatin, pazopanib and letrozole. 
     
     
         10 . The method according to  claim 1 , wherein said human shows a statistically significantly less hepatotoxicity when administered lapatinib, or a pharmaceutically acceptable salt or composition thereof, compared with a human having at least one polymorphism selected from the group of: HLA-DRB1*0701, HLA-DQA1*0201, HLA-DQB1*0202 and HLA-B*4403 and/or a human having a genotype in TNXB, rs12153855 and/or rs17207923. 
     
     
         11 . The method according to  claim 1 , wherein said human has both HLA-DQA1*0201 and HLA-DQB1*0202 polymorphisms. 
     
     
         12 . The method according to  claim 1 , wherein said human is DQ2.2. seropositive. 
     
     
         13 . The method according to  claim 1 , wherein said human does not show significant elevation in alanine aminotransferase (ALT) and/or total bilirubin (TBL) after the administration of at least one dose of lapatinib, or a pharmaceutically acceptable salt or composition thereof. 
     
     
         14 . A method of screening a human subject as an aid in predicting hepatotoxicity to lapatinib, or a pharmaceutically acceptable salt or composition thereof, administration, comprising determining whether the human has a HLA genotype associated with an increased risk of hepatotoxicity to lapatinib, or a pharmaceutically acceptable salt or composition thereof, compared to the risk expected in the general population, wherein the presence of such a HLA genotype indicates the human is at increased risk for a hepatotoxicity to lapatinib, or a pharmaceutically acceptable salt or composition thereof. 
     
     
         15 . A method according to  claim 14 , further comprising treating said human subject with a therapeutic regime of lapatinib, or a pharmaceutically acceptable salt or composition thereof, when the human subject is not at increased risk of a hepatotoxicity to lapatinib, or a pharmaceutically acceptable salt or composition thereof. 
     
     
         16 . A method according to  claim 14 , wherein the HLA genotype is selected from the group of: HLA-DQA1*0201, HLA-DQB1*0202, and HLA-DRB1*0701. 
     
     
         17 - 24 . (canceled) 
     
     
         25 . A method of treating a human subject in need of treatment with lapatinib, or a pharmaceutically acceptable salt or composition thereof, the method comprising:
 (a) determining the genotype of the human subject at the HLA-DQA1, HLA-DQB1, HLA-DRB1, and/or HLA-B regions of chromosome 6; and   (b) administering lapatinib, or a pharmaceutically acceptable salt or composition thereof, to said human subject if polymorphic allele in an HLA gene is not detected.   
     
     
         26 . The method according to  claim 25  where said human is suffering from cancer. 
     
     
         27 . The method according to  claim 25  where said HLA gene is a MHC Class II HLA gene. 
     
     
         28 . The method according to  claim 27 , wherein the polymorphic allele is selected from selected from the group of: HLA-DQA1*0201, HLA-DQB1*0202, and HLA-DRB1*0701. 
     
     
         29 . The method of  claim 28 , wherein said human has at least one additional polymorphic allele. 
     
     
         30 . The method according to  claim 28 , wherein said human has both HLA-DQA1*0201 and HLA-DQB1*0202 polymorphisms. 
     
     
         31 . A method for prescribing lapatinib, or a pharmaceutically acceptable salt or composition thereof, to a human subject diagnosed with a medical condition suitable for treatment with lapatinib, or a pharmaceutically acceptable salt or composition thereof, comprising:
 a. determining whether the human subject has at least one HLA genotype that has been associated with increased risk of hepatotoxicity, compared to the risk in the general population, and   b. where said human subject is not determined to have a genotype that has been associated with increased risk hepatotoxicity, prescribing treatment with lapatinib, or a pharmaceutically acceptable salt or composition thereof, to said human subject.   
     
     
         32 - 36 . (canceled) 
     
     
         37 . The method according to  claim 31 , wherein said HLA genotype is determined by a method that detects the presence of the allelic DNA sequence. 
     
     
         38 . A method of administering lapatinib, or a pharmaceutically acceptable salt or composition thereof, to reduce the incidence of hepatotoxicity, comprising:
 a. from a starting population of human subjects having a condition suitable for treatment with lapatinib, or a pharmaceutically acceptable salt or composition thereof, selecting a treatment population having a decreased percentage of subjects with an polymorphic allele in HLA compared to the starting population; and   b. administering lapatinib, or a pharmaceutically acceptable salt or composition thereof, to said treatment population;   
       whereby the incidence of hepatotoxicity is reduced in the treatment population compared to the incidence of hepatotoxicity that would be expected to occur in the starting population. 
     
     
         39 . A method of identifying a human subject at increased risk of experiencing a hypersensitivity reaction to a therapeutic regime of lapatinib, or a pharmaceutically acceptable salt or composition thereof, comprising:
 a. performing a genotyping technique on a biological sample from said subject to determine whether the human subject's HLA genotype includes an allele selected from HLA-DQA1*0201, HLA-DQB1*0202, or HLA-DRB1*0701;   b. detecting an HLA-DQA1*0201, HLA-DQB1*0202, and/or HLA-DRB1*0701; and   c. correlating the detection of an HLA-DQA1*0201, HLA-DQB1*0202, and/or HLA-DRB1*0701, allele with an increased risk of experiencing a hepatotoxicity to a therapeutic regime of lapatinib, or a pharmaceutically acceptable salt or composition thereof, compared to the risk if no HLA-DQA1*0201, HLA-DQB1*0202, and/or HLA-DRB1*0701, allele were detected.   
     
     
         40 . The method according to  claim 39  further comprising performing a genotyping technique on a biological sample from said human subject to determine whether the subject's has genotypes in TNXB rs12153855 and/or rs17207923 and correlating correlating the detection of an genotypes in TNXB rs12153855 and/or rs17207923 with an increased risk of experiencing a hepatotoxicity to a therapeutic regime of lapatinib, or a pharmaceutically acceptable salt or composition thereof, compared to the risk if no genotypes in TNXB rs12153855 and/or rs17207923 were detected. 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . The method according to  claim 39 , wherein said human is also free from (TA)7/(TA)7 genotype of UGT1A1. 
     
     
         44 . A method of treating a human for cancer comprising administering at least one dose of lapatinib, or a pharmaceutically acceptable salt or composition thereof, to said human, wherein said human is genotyped as not having one or more allelic polymorphisms selected from the group of: HLA-DQA1*0201, HLA-DQB1*0202 and HLA-DRB1*0701. 
     
     
         45 . A method of treating a human for cancer comprising administering at least one dose lapatinib, or a pharmaceutically acceptable salt or composition thereof, to said human, monitoring the level of ALT and/or bilirubin in said human's blood, genotyping said human for one or more allelic polymorphisms selected from the group of: HLA-DQA1*0201, HLA-DQB1*0202, and HLA-DRB1*0701, and/or genotypes in TNXB rs12153855 and/or rs17207923 if said human demonstrates an elevation in said ALT above 3×ULN and/or said total bilirubin 2.0×ULN. 
     
     
         46 . The method of  claim 44 , further comprising administering at least a second dose of lapatinib to said human if said human does not have one or more allelic polymorphisms selected from the group of: HLA-DQA1*0201, HLA-DQB1*0202, and HLA-DRB1*0701. 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . A method of administering lapatinib, or a pharmaceutically acceptable salt or composition thereof, to a human comprising:
 (a) administering at least a first dose of lapatinib, or pharmaceutically acceptable salt or composition thereof, to said human,   (b) monitoring at least one liver signal in said human,   (c) genotyping said human for one or more allelic polymorphisms selected from the group of: HLA-DQA1*0201, HLA-DQB1*0202, and HLA-DRB1*0701 if said liver signal becomes elevated after receiving at least one dose of lapatinib or pharmaceutically acceptable salt or composition thereof; and   (d) administering at least a second dose of lapatinib or pharmaceutically acceptable salt or composition thereof, to said human if the human does not have any of the polymorphisms of step (c).   
     
     
         50 . The method of  claim 49  wherein said liver signal is selected from ALT and TBL. 
     
     
         51 . (canceled) 
     
     
         52 . The method of  claim 49 , wherein said ALT is elevated to above about 3.0×ULN and/or TBL is elevated to above about 1.5×ULN after at least one dose of lapatinib. 
     
     
         53 - 56 . (canceled)