A phase I trial of erlotinib, gemcitabine and radiation for patients with locally advanced, unresectable pancreatic cancer

Abstract

4107 Background: Pre-clinical data indicates that inhibition of EGFR potentiates the effect of gemcitabine (gem) and radiation (RT) in pancreatic cancer cell lines. Based on this data, we are conducting a phase I trial to determine the maximal tolerated dose (MTD) of erlotinib (Tarceva), an oral EGFR TKI, in combination with gemcitabine and RT in patients with histologically-proven, locally-advanced unresectable pancreatic adenocarcinoma. Methods: Cohorts of 3–6 patients received escalating doses of erlotinib (100mg, 125mg) with gem (40mg/m2, biw) and RT (50.4 Gy in 28 fractions to the primary and regional nodes.) Four weeks following completion of chemoradiation (CRT), patients received maintenance chemotherapy with gem 1000 mg/m2 (d1, 8 every 21 days) and erlotinib 100 mg daily for 4 cycles. Eligibility criteria included laparoscopically-staged, locally-advanced disease; no prior therapy; normal organ and bone marrow function; ECOG PS ≤ 2. Toxicity was assessed during and for 2 weeks following CRT Results: Nine patients have been enrolled: M:F 3:6, median age 58 (range 45–79), median PS 1. Three patients received erlotinib at 100mg and 6 patients at 125mg. Common non-heme toxicities included fatigue, abdominal pain, nausea/vomiting, weight loss and rash. Grade 3/4 leukopenia (n=4) and thrombocytopenia (n=2) was observed only at erlotinib 125 mg. One patient at 100 mg (fever) and 2 patients at 125 mg (fever, N/V) were hospitalized while receiving CRT. DLT at the 125 mg dose level was observed in 2 patients: persistent myelosuppression which delayed completion of treatment beyond 7.5 weeks (n=1) and grade 3 transaminitis (n=1). Following CRT, 8 patients were evaluated for response radiographically: (7 SD, 1 POD). Of 6 patients with an elevated CA19–9 at baseline, 4 experienced a decrease by > 50%. One patient was referred for exploratory laparotomy and underwent an R1 resection. We are treating 10 additional patients at the MTD to better define toxicity and efficacy. Conclusions: The MTD of erlotinib in combination with gem 40mg/m2 biw and standard RT is 100mg daily. Correlative tissue stained by IHC for EGFR, pEGFR, HER2/neu, pAKT and PTEN will be presented. (Supported by ACS MRSG 04–239-01-CCE) No significant financial relationships to disclose.