A pharmacodynamic trial of sequential sunitinib (Su) with bevacizumab (Bev) in patients (Pts) with renal cell carcinoma and other advanced solid malignancies.

Abstract

434 Background: Su treatment results in a compensatory increase in plasma VEGF levels. Acute withdrawal of Su results in a proliferative withdrawal flare, primarily due to elevated VEGF levels. Higher flare corresponded to shorter PFS. Concurrent Su plus Bev is poorly tolerated with high (37%) incidence of microangiopathic hemolytic anemia (MAHA). Based on biological rationale and to improve the toxicity profile, we evaluated a sequential design administering Bev during the Su treatment break. We planned to evaluate the ability of Bev to suppress the Su withdrawal flare using FLT PET/CT. Methods: Pts with no prior VEGF treatment were enrolled in this multi-institutional study. All pts had target lesions amenable to serial FLT PET/CT imaging. Su was given at 37.5 mg on day 1-28 every 6 weeks with Bev 5 mg/kg on day 29. If safe and tolerable, Su would increase to 50 mg. Once the Su dose was established, FLT PET/CT scans would be obtained at baseline (D1), week 4, and week 6 to evaluate pharmacodynamics of the sequential combination. Su pharmacokinetics and total, free, and bound VEGF levels were obtained on each cycle at D1, pre-Bev (D29), 4 hours post Bev (D29H4) and day 42 (D42). Results: Six pts enrolled in the safety cohort of Su 37.5 mg plus Bev. One pt experienced gr 1 MAHA and after discussion with CTEP, the trial was closed to further accrual. No imaging scans were obtained due to early closure. Data assessing VEGF dynamics appears in the table. Conclusions: Subclinical MAHA was seen despite using sequential Su with low dose Bev and this combination was not feasible for further development. As predicted, VEGF levels increased during Su exposure followed by a rapid decline after Bev. Due to the long half-life of Bev, we expected VEGF ligand suppression through D42, but instead observed a complete rebound in total/free VEGF levels by D42. VEGF ligand production may be increased as a result of Bev, implying a robust host compensatory mechanism to VEGF signaling pathway inhibition. A greater understanding of the compensatory mechanism would aid future sequencing strategies of new agents. Clinical trial information: NCT01243359. [Table: see text]