Pharmacodynamic (PD) assessment of blood pressure (BP) in a randomized dose-ranging trial of sorafenib (S).

Abstract

3016 Background: Hypertension may be a PD marker for efficacy of VEGF signaling pathway (VSP) inhibitors. The effects of S doses >800 mg/d on BP are not well characterized. To determine precisely the BP response to escalated doses of S, advanced solid tumor patients (pts; ECOG PS < 2 and screening BP < 140/90 mmHg on no antihypertensives) underwent serial 12-hour ambulatory BP measurement sessions (ABP) on different doses of S. Methods: The primary objective was to detect an increase in diastolic BP (DBP) proportional to the increased dose (based on prior data, assumed mean DBP increase for 400 mg BID = 6.0; on increased dose = 9.0 mmHg). ABP were conducted pre/post 7 d of S 400 mg BID. All pts then received no drug for 7 d, followed by another ABP. Pts with no > grade 2 toxicities during the first 2 wks were then randomized to receive escalated dose S at 400mg TID or 600mg BID. All pts repeated ABP after 7 d of additional S. Readings were collected every 10 min during daytime hrs (minimum # readings for evaluable session = 50). Results: 54 of a planned 58 pts were evaluable for data analysis by January 2011. Mean DBP elevation from baseline to Day 7 was 8.0 (SD= 6.5; 95% CI 6.3-9.8) mmHg. The variance in the change in DBP during the washout phase was unexpected, with 32/54 pts having DBP return to baseline (BL); 15/54 had DBP remain elevated and 7/54 had DBP decline below BL. After the 7 d washout, 18 were randomized to 400 mg TID, 19 to 600 mg BID, and 17 received 400 mg BID again. To detect the dose escalation effects on ABP, Day 22 DBP was fit to a regression model with main effect terms for Day 7 DBP and Day 14 DBP and interaction terms for BL DBP, age, sex, race (AA vs. other), and BSA. The final model (R2= 0.73; p < 0.00001) included terms for BL, Day 7, and Day 14 DBP. Compared to 400 mg BID, mean DBP with 400 mg TID was 4.7 mmHg greater (p=0.15, 95% CI -1.7, 11). Mean DBP for the 600 mg BID arm was 2.6 mmHg greater (p=0.41, 95% CI -3.7, 8.8). The difference between the 2 dose escalation arms was not significant (p=0.25). Conclusions: Escalating S dose in a pt population did not uniformly lead to further DBP elevations. To enhance efficacy of S, and perhaps other VSP inhibitors, will likely require a more complex PD-based scheme than dose-to-hypertension.