Abstract A4: Phase I clinical trial evaluating the safety, pharmacokinetics and biological effect of intravenous bevacizumab (avastin) in combination with escalating doses of AZD2171 (cediranib) administered orally for 21 consecutive days to patients with advanced malignancies (NCI protocol #7534)
Authors: Hong David S. , Davis Darrin , Naing Aung , Fu Siqing , Falchook Gerald , Ricks Linda W. , Bekele Nebe , Mittleman David , Liu W. , Ivy Percy , Herbst Roy , Kurzrock Razelle 
Published: June 2012

Abstract
Background: Angiogenesis inhibitors may be classified as direct or indirect inhibitors. Direct inhibitors like bevacizumab (B) that target the microvascular endothelial cells and prevent them from responding to different endothelial mitogens. Conversely, indirect inhibitors like cediranib (C), target growth-factor tyrosine kinases and its VEGF receptors on tumor endothelium. We hypothesized that maximizing VEGF inhibition with a combination therapy consisting of a direct angiogenesis inhibitor (B) and an indirect inhibitor (C) with different VEGF blocking mechanisms may result in increased anti-tumor activity and a safe toxicity profile. As a first step, we conducted a phase I study of the combination of bevacizumab and cediranib in advanced cancer patients.
Methods: Pts with advanced solid tumors refractory to standard therapy were eligible. The trial is a conventional phase I 3+3 dose-escalation design. Cediranib was administered orally continuously for 21 days. Bevacizumab was given every two weeks (days 1 and 15) at escalating doses. Correlative studies including pharmacokinetic studies of cediranib, DCE-MRI, and circulating tumor (CTCs) and endothelial cells (CECs).
Results: A total of 27 pts have been treated. Dose level 3 (C-30 mg/day and B-5mg/kg/2 weeks) was determined to be the MTD with the major dose-limiting toxicity of hypertension. The most common drug related toxicities include hypertension (66%), fatigue (41%), and anorexia (33%). Currently, of the 17 evaluable pts by RECIST, 7 pts had SD for &gt;4 cycles (months). One confirmed PR was noted in a metastatic basal cell carcinoma pt (−33%) and one unconfirmed PR (−31%) in ovarian cancer pt. Several notable minor responses by RECIST have also been observed in the SD pts; 2 pts with RCC (−21%, −23%), an alveolar soft tissue sarcoma pt (−24%), and a prostate cancer pt (−21%). Overall, immature CECs (CD105+) enumerated by CellSearch™ revealed a dose-dependent significant decrease (1,290% to 93%; p=0.0001). A 3-fold induction in apoptosis was observed at 24 hrs compared to baseline in the CD105-positive CECs. Overall, mature CECs (CD31+) assessed for VEGFR2 activity revealed an 83% and 1.9% significant (p=0.019) inhibition in pVEGFR2 expression at low (B;3mg/kg) and high (B;5mg/kg) doses, respectively. In the non-responders, mature CECs revealed a dose-dependent (C;20mg/kg–30mg/kg) significant increase (−6.8% to 63%;p=0.031) in pERK/ERK expression levels. PK and DCE-MRI analysis is pending.
Conclusions: The MTD was determined to be cediranib 30mg/day and bevacizumab 5mg/kg/2weeks. Activity has been seen in a diverse number of tumor types. Inhibition of pVEGFR2 and induction of apoptosis in CECs shows target effect by the combination.
Grant support: National Cancer Institute grant and 2 UO1 CA062461-15
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A4.