Abstract P112: Mechanism of the Blood Pressure Response to a Novel Vascular Disrupting Combretastatin A1-Diphosphate (OXi4503)

Abstract

Background: Hypertension has been observed in cancer clinical trials of vascular disrupting agents (VDAs) but the mechanism is unknown; hence, prevention and management are difficult. Clearly, an improved understanding of the pathophysiology of blood pressure (BP) changes with VDAs would improve the standard of care for this novel class of anti-cancer agents. Accordingly, we hypothesized that VDAs may influence BP via activation of the angiotensin-renin system. Methods: Escalating doses of combretastatin A1-diphosphate (OXi4503) were given intravenously over 10 minutes on days 1,8,15 and 22 in 28-day cycles in a Phase IA trial of acute myeloid leukemia (AML) patients (NCT01085656). BP and plasma levels of angiotensin II (angII) were measured prior to and 0.5, 1, 2, 3, 4, 5, 6 and 24 hrs after infusion. If BP was ≥120/80 at baseline, amlodipine was administrated 60 minutes before OXi4503. Results: A total of 16 patients were treated: median age 63.5 years (range, 24-79); 12 were men. Two subjects received 2.5 mg/m 2 , two-3.75 mg/m 2 , nine-5 mg/m 2 and three-6.25 mg/m 2 . Most (9/16) had a history of HTN. SBP rose in all patients, reaching 140-159 mmHg in 5/16 (31.2%) and ≥160 mmHg in 3/16 (18.7%). In 11 patients pretreated with amlodipine, 5/16 (45.4%) developed SBP ≥140 mmHg. Prior HTN history and increasing age were predictors of the SBP response. In those with a HTN history, peak SBP was 151.717.2 (mean±SD) versus those without a HTN history (126.711.4, P = 0.003). At one hr after OXi4503 infusion, SBP correlated with the level of angII (Spearman: 0.53, CI95% (0.04-0.81) P= 0.03). Although there was no significant association between OXi4503 dose and percent maximal increase in SBP or level of angII, compare with baseline, there was a significant correlation between the dose and level of angll 0.5 hours after infusion (Spearman: 0.54, CI95% (0.07-0.82), P=0.02). In all patients, SBP returned to baseline by 24 hrs. Conclusion: The VDA OXi4503 increased BP and this may be mediated, in part, by angII signaling. Our findings suggest, for the first time, that selective angII receptor blockade is worth exploration for patients receiving VDAs.