CRENOLANIB BESYLATE IN D824V GIST

PLATELET-DERIVED GROWTH FACTOR RECEPTOR-A, MUTATIONS IN GIST

PDGFRAD842V GIST Background

  • Activating mutations in PDGFRA are seen in 8-10% of GIST1
  • PDGFRD842V is seen in 4-5% of GIST1
  • PDGFRD842V is intrinsically resistant to imatinib and sunitinib2

 

 

CRENOLANIB INHIBITION OF D842V MUTATED PDGFRA1

Crenolanib inhibits the phosphorylation of D842V mutated PDGRA at nanomolar concentrations in CHO cell lines
Crenolanib decreases proliferation of retrovirally transduced Ba/F3 cells stably expressing the PDGFRAD842V mutation

 

CRENOLANIB INHIBITS PHOSPHORYLATION OF D842V IN GLIAL CELLS3

 

 

CRENOLANIB DECREASES PROLIFERATION OF BA/F3 D842V MUTATED PDGFRA

Ba/F3 cells bearing mutant PDGFRA were incubated for 72 hours in the presence or absence of different concentrations of imatinib or crenolanib. Cell numbers were determined by CCK-8 proliferation assays. Results were presented as mean SD of triplicate samples.4

 

CLINICAL TRIALS

  • ARO-002

    Phase II Study of Crenolanib (CP-868,596), for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions in the PDGFRA Gene (NCT01243346)

    This Phase II study is designed to evaluate the antitumor efficacy and pharmacokinetics of crenolanib in patients with D842-related mutant metastatic GIST. Twenty patients were treated under this trial at Fox Chase Cancer Center and Oregon Health and Science University.

    For more information please see: clinicaltrials.gov


    A patient showed a marked reduction in glucose uptake after 20 days of crenolanib exposure5
     

  • ARO-012

    Phase III Monotherapy of Crenolanib in Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations

    This is a Phase III study of crenolanib in patients with advanced PDGFRA-D842 related gastrointestinal stromal tumors (GIST) opening in multiple centers in Europe.


1Heinrich et al. Clin Cancer Res. 2012; 18:4375-4384
2Debiec-Rychter et al. Eur J Cancer 2006; 42(8):1093-1103
3Paugh et al. J Clin Oncol. 2010; 28(18):3061-3068 (modified from)
4Dai et al. Clin Cancer Res. 2013; 19(24):6935-6942 (modified from)
5Matro et al., ASCO 2014