title: Accelerated disease progression in prostate cancer and bone metastases with platelet-derived growth factor receptor inhibition: observations with tandutinib.
abstract: BACKGROUND
  Activated platelet-derived growth factor receptor (p-PDGFR) is frequently expressed in bone metastases of castration-resistant prostate cancer (CRPC). Phase II study of tandutinib was conducted to assess the effects of a continuously administered highly potent PDGFR inhibitor in this disease state.
  
  
  METHODS
  Men with progressive CRPC, bone metastases, and prior taxane chemotherapy were treated with oral tandutinib 500 mg twice daily until disease progression under a two-stage design with the 8-week freedom-from-progression (FFP) rate as the primary endpoint. The trial was designed to have 87% power to reject a null FFP rate of 10% when the true rate was 33% (type I error rate = 0.02). Secondary endpoints included tumor expression of p-PDGFR, bone marker (urine N-telopeptide, serum bone-specific alkaline phosphatase) kinetics, in vivo monitoring of PDGFR inhibition in peripheral blood leukocytes, and correlation with survival.
  
  
  RESULTS
  Among 18 patients registered (aged 47-81, median 66 years), 15 were evaluable for efficacy. Five of 6 evaluable tumors were p-PDGFR positive. Mean urine N-telopeptide declined from 123.7 (baseline) to 41.0 (Cycle 2 Day 1) nmol/mmol Cr (P = 0.012). Probability of decrease in peripheral blood leukocyte p-PDGFR >0.5 versus <0.5 was associated with progression-free survival of 6 versus 8 weeks (P = 0.03, log-rank) and overall survival, 26.6 versus 42.9 weeks, respectively (P = 0.09, log-rank).
  
  
  CONCLUSIONS
  In vivo PDGFR inhibition with tandutinib correlated with accelerated disease progression. This observation raises the hypothesis that PDGF contributes to the homeostasis of bone metastases from prostate cancer.
authors.affiliation: Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. pmathew@tuftsmedicalcenter.org
authors.forename: Paul
authors.initials: P
authors.lastname: Mathew
authors.forename: Nizar
authors.initials: N
authors.lastname: Tannir
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Tu
authors.forename: Sijin
authors.initials: S
authors.lastname: Wen
authors.forename: Charles C
authors.initials: CC
authors.lastname: Guo
authors.forename: Valerie
authors.initials: V
authors.lastname: Marcott
authors.forename: Benjamin Nebiyou
authors.initials: BN
authors.lastname: Bekele
authors.forename: Lance
authors.initials: L
authors.lastname: Pagliaro
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D011799:Quinazolines; C464670:tandutinib; D017479:Receptors, Platelet-Derived Growth Factor