Serum C-Telopeptide Collagen Crosslinks and Plasma Soluble VEGFR2 as Pharmacodynamic Biomarkers in a Trial of Sequentially Administered Sunitinib and Cilengitide

Peter H. O'Donnell, Sanja Karovic, Theodore G. Karrison, Linda Janisch, Matthew R. Levine, Pamela J. Harris, Blase N. Polite, Ezra E.W. Cohen, Gini F. Fleming, Mark J. Ratain, Michael L. Maitland

Fit-for-purpose pharmacodynamic biomarkers could expedite development of combination anti-angiogenic regimens. Plasma sVEGFR2 concentrations ([sVEGFR2]) mark sunitinib effects on the systemic vasculature. We hypothesized that cilengitide would impair microvasculature recovery during sunitinib withdrawal and could be detected through changes in [sVEGFR2]. Advanced solid tumor patients received sunitinib 50 mg daily for 14 days. For the next 14 days, patients were randomized to Arm A (cilengitide 2000 mg administered intravenously twice weekly (BIW)), or Arm B (no treatment). The primary endpoint was change in [sVEGFR2] between Day 14 and Day 28. A candidate pharmacodynamic biomarker of cilengitide inhibition of integrin αvβ3, serum c-telopeptide collagen crosslinks (CTx), was also measured. Of 21 patients, 14 (7/arm) received all treatments without interruption and had all blood samples available for analysis. The mean change and standard deviation of [sVEGFR2] for all sunitinib-treated patients was consistent with previous data. There was no significant difference in the mean change in [sVEGFR2] from Day 14 to Day 28 between the arms (Arm A: 2.8 ng/mL [95% CI 2.1, 3.6] vs. Arm B: 2.0 ng/mL [95% CI 0.72, 3.4] P = 0.22, two sample t test). Additional analyses suggested: 1) prior bevacizumab therapy to be associated with unusually low baseline [sVEGFR2], and 2) sunitinib causes measurable changes in CTx. Cilengitide had no measurable effects on any circulating biomarkers. Sunitinib caused measurable declines in serum CTx. The properties of [sVEGFR2] and CTx observed in this study inform the design of future combination anti-angiogenic therapy trials.