Gdf-15 as a haematological toxicity biomarker

Abstract

The present disclosure relates to use of GDF-15 as a safety biomarker for determining a toxicological effect of a Mdm2 inhibitor; an ex vivo method for determining a toxicological effect of a Mdm2 inhibitor in a subject, in particular for determining a likelihood of developing thrombocytopenia in a subject in response to administration of a dose of a Mdm2 inhibitor; methods of using a Mdm2 inhibitor in the treatment of cancer in a subject; a kit for use in predicting the likelihood that a patient having cancer will develop thrombocytopenia in response to a treatment with a dose of a Mdm2 inhibitor; a kit for use in treating a patient having cancer and related disclosure embodiments.

1 . A method of preventing or treating drug-induced thrombocytopenia associated with murine double minute 2 (Mdm2) inhibitor administration in a subject, comprising the steps of:
 (i) providing a pre-administration biological sample obtained from said subject prior to administration of the Mdm2 inhibitor;   (ii) measuring expression of Growth differentiation factor 15 (GDF-15) in the pre-administration biological sample;   (iii) administering a continuous dose of said Mdm2 inhibitor to said subject;   (iv) providing a post-administration biological sample obtained from said subject after the administration of said Mdm2 inhibitor;   (v) measuring expression of GDF-15 in the post-administration biological samples;   (vi) comparing expression of GDF-15 in the pre-administration biological sample with the level of expression of GDF-15 in the post-administration biological sample; and   (vii) administering a thrombopoietin receptor agonist to said subject when the GDF-15 expression in the post-administration biological sample is at least 25% higher in comparison with the GDF-15 expression in the pre-administration biological sample.   
     
     
         2 - 5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the thrombopoietin receptor agonist is eltrombopag. 
     
     
         7 . The method of  claim 1  wherein the Mdm2 inhibitor is (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 1  wherein the Mdm2 inhibitor is (S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one, or a pharmaceutically acceptable salt thereof.