PDGFR Summary

Platelet derived growth factor receptors (PDGFRs) are tyrosine kinase receptors, that are involved in many normal cellular processes, including organogenesis, cell proliferation, angiogenesis, etc. These receptors come in two isoforms called PDGFRA and PDGFRB. PDGFR signaling can be altered by gene amplification or activating mutations. These aberrations in PDGFR have an incidence of about 30% in cancer. Tumor types for which PDGFR is altered in at least 10% of cases includes GIST, glioblastoma, lung, melanoma, bladder, prostate, colorectal and ovarian cancers.

What is GIST?

Gastrointestinal stromal tumor (GIST) is a disease in which abnormal cells form in the tissues of the gastrointestinal tract: stomach, small intestine, and large intestine. GIST is the most common sarcoma of the gastrointestinal (GI) tract.

In approximately 5% of patients with GIST, defects in a gene called PDGFRα, known as D842V, lead to primary resistance to existing approved medications. Currently, there are no approved targeted therapy options for PDGFRα D842V mutant GIST.

Prior results have demonstrated the clinical safety and efficacy of crenolanib in patients with PDGFRα D842V mutant GIST

Crenogist (ARO-012): an ongoing study for D842V Mutant GIST

  • This is a Phase III clinical trial of crenolanib in patients with advanced or metastatic gastrointestinal stromal tumors (GIST) with a specific mutation (D842V) in the PDGFRA gene.
  • This study is currently recruiting at multiple centers in the United States and Europe.
  • This study aims to find out how safe and effective crenolanib is, compared with a placebo, in prolonging the amount of time patients avoid disease progression.

For more information about the study, please contact a study site or visit clinicaltrials.gov/ct2/show/NCT02847429

Recent Conference Presentations

  1. Blay, J.-Y., Heinrich, M.C., Hohenberger, P., Casali, P.G., Rutkowski, P., SerranoGarcia, C., Jones, R.L., Hall, K.S., Eckardt, J.R., and Mehren, M.v. (2017). A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of Crenolanib in Advanced or Metastatic GIST Patients Bearing a D842V Mutation in PDGFRA: The CrenoGIST Study. In ASCO Annual Meeting.
  2. Colletti, E., Ramachandran, A., Carter, M., and Ward, S. (2013). Crenolanib inhibition of PDGFRA+ fibroblast-like cells in visceral smooth muscle. In American Association for Cancer Research.
  3. Hayashi, Y., Bardsley, M.R., Toyomasu, Y., Choi, K.M., Taguchi, T., Ramachandran, A., Gibbons, S.J., Farrugia, G., and Ordog, T. (2012). Effects of Crenolanib, a Highly Selective Platelet-Derived Growth Factor Receptor α/β (PDGFRA/B) Tyrosine Kinase Inhibitor, on the Proliferation of Kii-Mutant Gastrointestinal Stromal Tumor (GIST) Cells and Interstitial Cell of Cajal (ICC) Precursors. In American Gastroenterology Association.
  4. Hayashi, Y., Bardsley, M.R., Toyomasu, Y., Taguchi, T., Rubin, B.P., Carter, M., Ramachandran, A., and Ordog, T. (2013). Crenolanib, a highly selective platelet-derived growth factor receptor α/β (PDGFRA/B) tyrosine kinase inhibitor, destabilizes ETV1 protein in KIT-mutant gastrointestinal stromal tumor (GIST) cells. In AACR Annual Meeting.
  5. Heinrich, M., Griffith, D., A.McKinley, Presnell, A., Ramachandran, A., Muralidhara, C., and Mehren, M.v. (2011a). Efficacy of crenolanib against the pdgfra activating mutation, d842v, associated with gastrointestinal stromal tumors. In Connective Tissue Oncology Society.
  6. Heinrich, M.C., Griffith, D., McKinley, A., Presnell, A., and Ramachandran, A. (2011b). The effect of crenolanib (CP-868596) on phosphorylation of the imatinib-resistant D842V PDGFRA activating mutation associated with advanced gastrointestinal stromal tumors. In ASCO Annual Meeting.
  7. Mehren, M.v., Heinrich, M., Tetzlaff, E., Padavic-Shaller, K., Yu, M., Muralidhara, C., and A.Ramachandran (2011). Abstract: Preliminary report of crenolanib in the treatment of advanced platelet derived growth factor a (PDGFRa) d842v mutant gastrointestinal stromal tumor (GIST). Presented at CTOS 2011.
  8. Muralidhara, C., Ramachandran, A., and Jain, V.K. (2014). Abstract 3683: Crenolanib, a novel Type I, mutant-specific inhibitor of Class III receptor tyrosine kinases, preferentially binds to phosphorylated kinases. Cancer Research 72, 3683-3683.
  9. Ramachandran, A., Muralidhara, C., and Jain, V.K. (2012). Crenolanib, a novel Type I, mutant-specific inhibitor of Class III receptor tyrosine kinases, preferentially binds to phosphorylated kinases. In Cancer Research, pp. 3683-3683.
  10. von Mehren, M., Heinrich, M., Tetzlaf, E., Padavic-Shaller, K., Walker, T., Granat, S., Yu, M., Muralidhara, C., and Ramachandran, A. (2011). Preliminary report of crenolanib in the treatment of advanced platelet derived growth factor A (PDGFRA) D842V mutant gastrointestinal stromal tumor (GIST). In CTOS Annual Meeting.
  11. von Mehren, M., Tetzlaff, E.D., Macaraeg, M., Davis, J., Vartika, A., Abhijit, R., and Heinrich, M.C. (2016). Dose escalating study of crenolanib besylate in advanced GIST patients with PDGFRA D842V activating mutations. J Clin Oncol 34 (suppl; abstr 11010).

Recent Peer-reviewed Publications

  1. Blay J-Y, Heinrich MC, Hohenberger P, et al. A randomized, double-blind, placebo-controlled, phase III study of crenolanib in advanced or metastatic GIST patients bearing a D842V mutation in PDGFRA: The CrenoGIST study. J Clin Oncol 2017; 35 (suppl; abstr TPS11080).
  2. von Mehren M, Tetzlaff ED, Macaraeg M, et al. Dose escalating study of crenolanib besylate in advanced GIST patients with PDGFRA D842V activating mutations. J Clin Oncol 2016; 34 (suppl; abstr 11010).
  3. Matro JM, Yu JQ, Heinrich MC, Ramachandran A, Ku N, Mehren Mv. Correlation of PET/CT and CT RECIST response in GIST patients with PDGFRA D842V gene mutations treated with crenolanib. J Clin Oncol 2014; 32:5s (suppl; abstr 10546).
  4. Heinrich MC, Griffith D, McKinley A, et al. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumorsClin Cancer Res 2012; 18(16): 4375-84.
  5. Michael M, Vlahovic G, Khamly K, Pierce KJ, Guo F, Olszanski AJ. Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor. Br J Cancer 2010; 103(10): 1554-61.
  6. Lewis NL, Lewis LD, Eder JP, et al. Phase I study of the safety, tolerability, and pharmacokinetics of oral CP-868,596, a highly specific platelet-derived growth factor receptor tyrosine kinase inhibitor in patients with advanced cancers. J Clin Oncol 2009; 27(31): 5262-9.