Novel phase I dose de-escalation design trial to determine the biological modulatory dose of the antiangiogenic agent SU5416

Afshin Dowlati, Kelly Robertson, Tomas Radivoyevitch, John Waas, Nicholas P. Ziats, Paul Hartman, Fadi W. Abdul-Karim, Jay K. Wasman, Jack Jesberger, Jonathan Lewin, Keith McCrae, Percy Ivy, Scot C. Remick

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Purpose: To determine the biological modulatory dose of SU5416, we employed a novel trial design, where "dose de-escalation" was based on demonstrable biological changes observed at the maximum tolerated dose. If such an effect was shown, dose de-escalation to a predefined dose level would occur to determine if the lower dose exhibited the same amount of pharmacodynamic effect as the higher dose. Experimental Design: Ten patients with advanced solid tumors were enrolled at each dose level. One of the following pharmacodynamic effects was considered significant: (a) a 35% decrease in microvessel density in sequential tumor biopsies and (b) a 35% decrease in blood flow within tumor as assessed by dynamic contrast-enhanced magnetic resonance imaging. In addition, soluble E-selectin, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule, and plasma vascular endothelial growth factor were measured sequentially. Results: Nineteen patients were enrolled. Sequential tumor biopsies in all evaluable patients showed an increase in microvessel density. Only one patient met the intended pharmacodynamic end point of >35% reduction in blood flow. There was a significant increase in both soluble E-selectin and soluble intercellular adhesion molecule levels pretreatment versus levels at the time of removal of patients from study (P = 0.04 and P = 0.0007, respectively). Levels of serum fibrinogen rose with therapy. There was a trend toward increase in plasma vascular endothelial growth factor levels. Conclusion: SU5416 does not result in decreased blood flow in tumors or a decrease in microvessel density. This corresponds to the lack of clinical activity seen with this agent. Our clinical trial design termed dose de-escalation is a novel approach to determine the in vivo biological effects of targeted therapies in cancer patients.

Original languageEnglish (US)
Pages (from-to)7938-7944
Number of pages7
JournalClinical Cancer Research
Issue number21
StatePublished - Nov 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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