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

<div><p>Purpose</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation.</p></div

CONSORT flow diagram of phase I trial.

<p>CONSORT flow diagram of phase I trial.</p

Exclusion criteria.

<p>Exclusion criteria.</p

Inclusion criteria for enrollment in the study.

<p>Inclusion criteria for enrollment in the study.</p

Kaplan-Meier estimates of (a) overall survival, (b) distant progression-free survival and (c) local progression-free survival from start of chemoradiation therapy.

<p>Kaplan-Meier estimates of (a) overall survival, (b) distant progression-free survival and (c) local progression-free survival from start of chemoradiation therapy.</p

Individual toxicity grade.

<p>Individual toxicity grade.</p

Toxicity by dose level.

<p>Toxicity by dose level.</p

Study Schema.

<p>Study Schema.</p

Patient characteristics.

<p>Patient characteristics.</p