Phase I Trial of Consolidative Radiotherapy with Concurrent Bevacizumab, Erlotinib and Capecitabine for Unresectable Pancreatic Cancer.

PURPOSE: To determine the safety, tolerability and maximum tolerated dose (MTD) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation (CRT) in unresectable pancreatic cancer.

METHODS: Seventeen patients with CT-staged, biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010. Prior chemotherapy was permitted. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose of each drug was escalated in 5 DLs using the continual reassessment method. Bevacizumab was escalated from 5mg/Kg q2weeks (DLs 1-4) to 10mg/Kg q2weeks (DL 5); daily erlotinib from 100mg/day (DLs 1-2) to 150 mg/Kg (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 650mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later.

RESULTS: Sixteen patients received gemcitabine-based chemotherapy prior to CRT. With a median clinical follow-up of 10 months, no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrhea, 1 rash). No grade 4 or 5 toxicities were seen. DL 4 was selected as the MTD; therefore, the recommended doses in combination with radiation are: bevacizumab, 5mg/Kg q2weeks; erlotinib, 150 mg/Kg daily; and capecitabine, 825mg/m2 BID. Median survival was 17.4 months. Of the five patients who underwent resection, 4 were originally deemed locally advanced and 1 was borderline resectable. Three patients had excellent pathological response (2 complete response and 20% viable tumor) at surgery, and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures.

CONCLUSIONS: This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation.