Background: Radiation exposure upregulates VEGF expression which protects endothelial cells from the effects of radiation therapy. Combining an angiogenesis inhibitor with radiation therapy may help to suppress VEGF expression and enhance antitumor activity. Aflibercept is an antiangiogenic agent that binds to VEGF-A, VEGF-B and placental growth factor. This phase II, non-randomized study combined ziv-aflibercept (aflibercept outside the US) with chemoradiation as preoperative treatment for pts with stage II/III rectal cancer, followed by 4 months of mFOLFOX6 plus ziv-aflibercept. Methods: Pts with stage II/III adenocarcinoma of the rectum received preoperative 5-FU (225 mg/m² IVCI, days 1-42), radiation (50.4 Gy, Mon.-Fri., weeks 1-6), and ziv-aflibercept (4 mg/kg IV, days 1-15) each 28 day cycle for 6 weeks. Six weeks from last dose of ziv-aflibercept, pts underwent surgical resection. Treatment with mFOLFOX6 plus ziv-aflibercept began 8 weeks after surgery for 4 cycles. The primary objective was to evaluate the pathologic complete response (pCR) rate. Secondary objectives included overall survival (OS), disease-free survival (DFS), sphincter preservation (SP) rate, and safety. Results: Thirty-nine pts were treated: median age 60 yrs (range, 36-89), 64% male, 82% ECOG 0, 69% stage III. Ninety-five percent of pts received preoperative treatment, 82% underwent resection, and 54% received postoperative treatment. The most common treatment-related toxicities (% G1/2; % G3/4) included diarrhea (51%; 21%), fatigue (59%; 5%), mucositis (38%; 15%), nausea (46%; 0), and hypertension (13%; 21%). Three postoperative complications of G3 pelvic abscess (2) and G3 GI fistula (1) were seen. Of the 32 pts resected, 8 pts (25%) achieved pCR, and pathologic partial response was seen in 24 pts (75%: 9 macroscopic, 15 microscopic). The SP rate was 72%; 31 pts (97%) had R0 resection. Median OS/DFS have not yet been reached. Conclusions: The 5-FU-based chemoradiation therapy combined with ziv-aflibercept in localized rectal cancer pts was well tolerated and showed a pCR rate in range with historical data. Median DFS is pending. Clinical trial information: NCT01749956