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Annals of Oncology Advance Access originally published online on September 17, 2007
Annals of Oncology 2008 19(1):86-91; doi:10.1093/annonc/mdm441
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© 2007 European Society for Medical Oncology. For Permissions, please email: journals.permissions@oxfordjournals.org

gastrointestinal tumors

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

A. Duffy1, J. Kortmansky2, G. K. Schwartz1, M. Capanu3, S. Puleio4, B. Minsky5, L. Saltz1, D. P. Kelsen and E. M. O'Reilly1,*

1 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
2 Medical Oncology and Hematology, New Haven, CT
3 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY
4 Clinical Trials Office, Memorial Sloan-Kettering Cancer Center, New York, NY
5 Department of Radiation Oncology, University of Chicago Medical Center, Chicago, IL, USA

* Correspondence to: Dr E. M. O'Reilly, Department of Medicine, Gastrointestinal Oncology Solid Tumor Service, Memorial Sloan-Kettering Cancer Center, Box 324, 1275 York Avenue, NY 10021, USA. Tel: +1-212-639-6672; Fax: +1-212-717-3320; E-mail: oreillye{at}mskcc.org

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/m2/30 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/m2 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/m2 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.

Key words: chemoradiation, erlotinib, gemcitabine, pancreas cancer, phase I

Received for publication June 8, 2007. Revision received August 6, 2007. Accepted for publication August 9, 2007.


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