Background: Axitinib (AX) is a potent inhibitor of receptor tyrosine kinases (RTK) of VEGFR-1,2,3. We previously showed that exposure to AX resulted in a decrease in tumor proliferation and vascular parameters, and during acute AX withdrawal, a rebound flare (proliferative and vascular) was present during cycle 1 (C1). Here we evaluate the impact of AX dose on the rebound pharmacodynamics, as well as assess whether this flare persists in later cycles of therapy with AX using an intermittent therapy schedule. Methods: Pts with prostate cancer or other advanced solid malignancies were enrolled. In the safety cohort, AX was administered at 7 mg BID on a 2 week on, 1 week off schedule. In the PD cohort, static/dynamic FLT PET/CT scans were obtained at baseline, week 2 (on AX), and wk 3 (off AX) in C1, and repeated again in C3 (pre-day 1, wk 2, wk 3). Plasma VEGF and AX PK levels were obtained at each imaging timepoint. Results: 24 pts were enrolled (safety cohort n = 8, PD cohort n = 16). Pts in the safety cohort received AX starting at 7 mg BID. Three pts developed significant hypertension and thrombovascular events; hence it was not felt that this starting dose was appropriate. For the PD cohort, AX dose was administered at 5 mg BID. 14 pts had scans on C1, and 5 pts completed scans during C3. Similar changes in proliferation/vasculature parameters were seen in C1 as previously reported. Decreases in proliferation/vasculature parameters were also seen in C3 (on AX) with rebound flare present at wk 3. Conclusions: Although dose-escalation of AX (up to 10 mg BID) has been shown to be feasible in renal cell cancer, use of intermittent AX at a starting dose of 7 mg BID was not feasible in our non-RCC pt population. We confirm previous findings that AX exposure results in a decrease in proliferation/vasculature parameters and that acute AX withdrawal results in a tumor/vasculature flare. We show with ongoing intermittent AX therapy, a similar PD change was observed in pts during C3. This result supports a sequential strategy of using intermittent AX in combination with S-phase specific chemotherapy in order to exploit the tumor/vasculature rebound in order to improve the therapeutic index of the cytotoxic chemotherapy. Clinical trial information: NCT01540526