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.