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 treating cancer in a subject with a murine double minute 2 (Mdm2) inhibitor, comprising the steps of:
 (i) providing a pre-administration biological sample obtained from said subject prior to administration of an Mdm2 inhibitor;   (ii) measuring expression of Growth differentiation factor 15 (GDF-15) expression 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) altering of the treatment of 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; or   (viii) making no changes to the administration regimen of said Mdm2 inhibitor to said subject, when the GDF-15 expression in the post-administration biological sample is less than 50% higher in comparison with the GDF-15 expression in the pre-administration biological sample.   
     
     
         2 . The method according to  claim 1 , wherein said alteration of the treatment comprises altering the administration regimen of said Mdm2 inhibitor to the subject, administering a means for reducing the Mdm2 inhibitor effect on thrombocytes, or altering the administration regimen of said Mdm2 inhibitor to the subject and administering a means for reducing the Mdm2 inhibitor effect on thrombocytes. 
     
     
         3 . The method according to  claim 1 , wherein said alteration of the treatment comprises a reduction of a dose of said Mdm2 inhibitor, a reduction of frequency of administration of said Mdm2 inhibitor, or a reduction of a dose of said Mdm2 inhibitor and a reduction of frequency of administration of said Mdm2 inhibitor. 
     
     
         4 . The method according to  claim 2 , wherein the means for reducing the Mdm2 inhibitor effect on thrombocytes comprises platelet transfusion, administration of thrombopoietin, administration of thrombopoietin receptor agonist, platelet transfusion and administration of thrombopoietin, platelet transfusion and administration of thrombopoietin receptor agonist, administration of thrombopoietin and administration of thrombopoietin receptor agonist, or platelet transfusion and administration of thrombopoietin, and administration of thrombopoietin receptor agonist. 
     
     
         5 . The method according to  claim 4 , wherein the means for reducing the Mdm2 inhibitor effect on thrombocytes comprises administration of a thrombopoietin receptor agonist, and wherein said thrombopoietin receptor agonist is eltrombopag. 
     
     
         6 . The method according to  claim 1 , wherein said alteration of the treatment comprises a discontinuation of treatment with said Mdm2 inhibitor. 
     
     
         7 . The method according to  claim 1 , wherein said alteration of the treatment comprises a drug holiday.