A Study of 7 Day's of Erlotinib Before Surgery, Followed by After Surgery Erlotinib-gemcitabine in Patients With Pancreatic Cancer

Our current clinical trial proposal includes a short course of pre-operative, single agent
erlotinib followed by post-operative erlotinib-gemcitabine in a neo-adjuvant/adjuvant
approach to the treatment of patients with resectable pancreatic adenocarcinoma. The short
course pre-operative erlotinib treatment serves two objectives: 1) erlotinib, through its
cytostatic effects, may hinder the ability of tumor cells to metastasize at the time of
surgical resection with minimal toxic effects and no delay in surgical treatment; 2) the
true effects of erlotinib on potential determinants of response can be best assayed on the
pancreatic cancer itself since no other model can better resemble the patients authentic
tumor microenvironment. The post-operative treatment component of the protocol attempts to
improve the demonstrated effects of gemcitabine by adding erlotinib in the adjuvant setting,
a drug combination that, as mentioned, has already been proven to be advantageous for
patients with advanced pancreatic cancer.

Traditionally, chemotherapy for cancer has been conducted in an empiric fashion by first
selecting a regimen based on clinical trial evidence and clinical parameters, and then by
assessing the objective response to that regimen employing clinical and radiographic imaging
means. This approach suffers from many disadvantages, most conspicuously the inability to
select the better patient candidates prior to the initiation of therapy, thus sparing the
risk and expense of ineffective treatment for patients who are unlikely to respond. Since
pancreatic cancer expression of EGFR protein by itself is not predictive of therapeutic
response, alternative methods of patient selection seem to be essential for the success of
EGFR-targeted treatment. The understanding of EGFR molecular signaling has allowed the drug
development process to shift from an empiric random screening approach to a more rational
and mechanistic, target-directed approach. Among multiple attempts to identify molecular
determinants of tumor cell sensitivity to EGFR inhibitors, there are two main paradigms that
stand out: 1) activation of downstream pharmacodynamic effectors associated with response to
the drug (i.e. phosphorylation of Akt or ERK; expression of c-fos), and 2) prediction of
sensitivity based on a "static" analyte (detection of EGFR sensitizing mutations;
epithelial-mesenchymal transition profile). However, given the complexity of factors
governing pancreatic cancer response to erlotinib, the biologic heterogeneity of malignant
phenotype, and overall relatively low response rates, we believe that it is unlikely that
analysis of a single biomarker will be useful for patient selection. A comprehensive
analysis of a dynamic panel of biomarkers relevant to EGFR signaling and erlotinib mechanism
of action seems more useful in that sense. Furthermore, the limited ability of pancreatic
cancer tissue sampling often precludes biomarker correlation to assays worked out in
xenograft models or in-vitro conditions.

The translational rationale of this proposal is therefore to develop predictive chemotherapy
sensitivity-resistance assays (CSRA) for pancreas carcinoma patients treated with erlotinib
and gemcitabine. This will represent a major advance, because the CSRA would enable
prediction of clinical response prior to initiation of therapy.