A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma

Abstract

Purpose: To determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity profile of this combination and secondarily evaluate response, time to tumor progression and overall survival. Methods:Patients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination with gemcitabine 40 mg/m 2 /30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m 2 on days 1 and 8 of a 21 day cycle and daily erlotinib for four cycles.Results: Three patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable disease. The median survival for all patients was 18.7 months. Conclusion:In combination with fixed dose gemcitabine at 40 mg/m 2 twice weekly and radiation at 180 cGy/day, the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in a poor prognostic cancer.

Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer – a multi-centre randomised phase II study

“…Moreover, novel innovative CRT regimens for LAPC including newer agents (e.g. oral fluoropyrimidines and biologicals) are currently under investigation in phase I and II clinical trials (Crane et al, 2006;Duffy et al, 2008;Kim et al, 2009;Michael et al, 2009). …”

Mitochondria as targets in angiogenesis inhibition

“…Erlotinib is a highly selective tyrosine kinase inhibitor that is approved for the treatment of patients with locally advanced or metastatic non-small cell lung carcinoma (NSCLC) after failure of at least one prior chemotherapy regimen (Herbst and Sandler, 2008). It is also approved in combination with Gemcitabine for the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer (Duffy et al, 2008). Another tyrosine kinase inhibitor, Gefitinib was also approved as a third-line option for patients with NSCLC.…”

Erlotinib

“…One study examined erlotinib plus gemcitabine and paclitaxel plus radiation followed by maintenance with erlotinib and reported a partial response rate of 46 % and median survival time of 14 months (Iannitti et al 2005). These results are supported by the other trial of erlotinib plus gemcitabine and radiation for patients with locally advanced, unresectable pancreatic cancer (Duffy et al 2008). Single-agent gemcitabine is the standard firstline agent for the treatment of advanced inoperable pancreatic cancer with a marginally superior clinical benefit and survival compared with fluorouracil (FU) approximately 10 years ago (Burris et al 1997).…”