Phase I trial of bevacizumab (BV) with concurrent radiotherapy (RT) and capecitabine (CAP) in locally advanced pancreatic adenocarcinoma (PA)

Abstract

4033 Background: Pancreatic cancers are resistant to RT. Vascular endothelial growth factor (VEGF) is overexpressed in many tumor types incuding PA. In vivo studies have shown that neutralizing VEGF activity can overcome radioresistance. Methods: Eligible patients for this phase I dose escalation trial had locally advanced, inoperable PA (AJCC 2002 T4, n=45), were inoperable based on pre-referral surgical exploration (T3, n=2) or medical comorbidity (n=1). Prior chemotherapy was allowed (n=25). An initial dose of BV (5 mg/kg IV) was administered 2 weeks prior to RT and every 2 weeks thereafter in successive cohorts of patients (12 patients each at 2.5, 5, 7.5, and 10 mg/kg) during RT (50.4 Gy to the primary tumor with capecitabine [650 mg/m2 PO BID (n = 6); 825 mg/m2 for the remaining patients]. Weekend doses of CAP were omitted in the final 12 patients. BV was continued (5 mg/kg IV q 2 wks) after RT until progression. Results: The worst acute gastrointestinal toxicity was grade 2 in 43% and grade 3 in 5% of patients. Two patients (5%) developed grade 3 hematologic toxicity and 24% developed grade 2 hand and foot syndrome. All patients completed RT and concurrent BV; (43%) of patients had at least a protocol-specified 25% dose reduction of CAP due to toxicity. Three patients had tumor-associated duodenal ulceration with bleeding [3, 10 (fatal), and 20 weeks after RT], and one had a contained duodenal perforation 10 weeks after RT). Primary tumor response: 9 of 41 evaluable had confirmed partial response (22% PR), 7 (17%) had minor response, 24 (59%) had stable disease and 2 (5%) had progressive disease. PR lasted until distant progression (median 6.2 months). Overall, only 5 patients have had local progression. Three patients have safely undergone pancreaticoduodenectomy. Median, 1 yr and 18 mo actuarial survival estimates were 15.7, 65% and 42% from the start of any therapy and 11.6, 45% and 29% from protocol entry. Conclusions: The addition of BV did not significantly increase the acute toxicity of a relatively well-tolerated chemoradiation regimen. Preliminary efficacy results are encouraging. Multiinstitutional studies are planned (RTOG PA 0411 and ACOSOG Z5041). Supported by Genentech Inc. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Labs Genentech