Reductions in platelet counts were analyzed in the three ongoing Phase I trials as a biomarker of Bcl-2 family protein inhibition. Subjects received doses ranging from 10 mg to 315 mg. The study data demonstrate that ABT-263 induces a transient decrease in circulating platelets via inhibition of Bcl- XL, without decreasing platelet production, confirming on-target activity. At 315 mg, researchers observed a 69 percent reduction in mean platelets from baseline values. Typically, platelet nadir occurred on days three to five with recovery during continued dosing. Tumor regression was observed in six patients, with three patients showing more than 50 percent tumor shrinkage. Adverse events included three dose-limiting toxicities, one Grade 3 URI at 160 mg, one Grade 3 alanine aminotransferase (ALT) elevation at 315 mg and one fatal respiratory failure at 10 mg. Updated information will be presented at the ASCO Annual Meeting.
Twenty-four patients from a completed Phase I trial (ABT-869), which
studied three dose levels of ABT-869, were evaluated to compare two
different measures of angiogenesis using functional imaging -- the
distributed parameter (DP) model and the transfer constant (Ktrans) model.
DP is a dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)
model that enables derivation of blood flow and capillary
permeability-surface area product (PS). Tests indicated that time over
threshold could be an important predictor of efficacy, and results
demonstrated that an appropriate value for the plasma concentration
threshold could be 0.08 ug/mL, with time above threshold value of
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