Phase I study of neoadjuvant bevacizumab, 5-fluorouracil, and radiation therapy followed by surgery for patients with primary rectal cancer

Abstract

3589 Background: Vascular endothelial growth factor (VEGF) is over expressed in rectal cancer and is associated with disease progression and inferior survival. Based on our pre-clinical studies, inhibition of VEGF may enhance radiation and chemotherapy response in patients with rectal cancer. To test this hypothesis, we initiated a phase I clinical trial in collaboration with the National Cancer Institute to evaluate the feasibility of integrating Bevacizumab (BV - a recombinant, humanized antibody against VEGF) into a contemporary treatment program of preoperative chemotherapy and radiation therapy followed by surgery for patients with primary and non-metastatic rectal cancer. Methods: Nine patients with clinical stage T3 or T4 NX M0 rectal cancer have completed a treatment program of preoperative BV (5mg/kg - 6 patients) or (10 mg/kg -3 patients) on day 1 followed by concurrent administration of BV (5 mg/kg or 10 mg/kg; days 15, 29, 43) with 5-fluorouracil (5-FU) chemotherapy (225 mg/m2 q24 hrs: days 15 –52) and radiation therapy (50.4 Gy in 28 fractions: days 15–52). Surgery is performed 7 weeks after completion of BV, 5-FU, and radiation therapy. Results: All six patients at dose level 1 of 5 mg/kg BV completed the protocol without dose limiting toxicity (DLT) and underwent resection without complication. Three patients have completed dose 2 of 10 mg/kg BV without DLT and one patient has undergone resection without complication. Two patients are scheduled for surgery. Endoscopic responses (just prior to surgery) have shown no visible macroscopic tumor in 6 of 7 evaluable patients. Similarly, pathological evaluation has demonstrated limited microscopic disease in the surgical specimens of 6 of 7 evaluable patients. Conclusions: Preliminary data (i) indicate safety of BV in combination with neoadjuvant 5-FU and radiation and surgery in the treatment of patients with locally advanced rectal cancer and (ii) significant clinical activity. (Supported by R21 CA099237 (Willett)). Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech