A Phase I Study of Erlotinib in Patients With Premalignant Lesions of the Lung
I. To determine the lowest dose of erlotinib that will decrease the ratio of phosphorylated
to total EGFR (pEGFR/EGFR) by at least 20% in subjects with premalignant lesions of the
lung. This will be accomplished by implementing a dose de-escalation trial of erlotinib
(i.e., 75, 50, and 25 or 100 mg by mouth daily for a 3-month period), and determining the
pEGFR/EGFR ratio in premalignant lesions of the lung epithelium by immunohistochemistry.
Changes in the pEGFR/EGFR ratio will be assessed by comparing the pre-treatment (baseline)
ratio to that of the post-treatment (3 month) ratio, measured in paraffin embedded biopsy
I. To determine the effect of erlotinib on the following biomarkers of potential biological
relevance in paraffin embedded lung biopsies, p-Akt, p-Erk, and Ki67.
II. To characterize the toxicity profile of erlotinib in this cohort of subjects.
III. To analyze and model erlotinib's pharmacokinetic/pharmacodynamic (PK/PD) profile.
Serial blood samples will be drawn at the beginning and at the end of erlotinib treatment,
and pharmacokinetic parameters will be determined. The status of EGFR genotype (and that of
others genes linked to erlotinib PK/PD) clinical toxicity, and dose will be examined as
possible other influential covariates by comparing them to experimentally measured PK
profiles, and PD profiles (in particular, the pEGFR/EGFR ratio). The goal of these studies
will be to determine the optimal biologic concentration (OBC) of Erlotinib that is
associated with the lowest toxicity and highest effect, for a given subject's
OUTLINE: Patients are stratified according to smoking status (current vs former/never
Patients receive oral erlotinib hydrochloride once daily for 90 days in the absence of
disease progression or unacceptable toxicity.
Patients undergo blood sample collection periodically for correlative biomarker,
pharmacokinetic, and pharmacogenetic studies.
After completion of study treatment, patients are followed up at 30 days.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Change in the ratio of p-EGFR to total EGFR
Up to 90 days
United States: Food and Drug Administration
|Roswell Park Cancer Institute||Buffalo, New York 14263|
|Northwestern University||Chicago, Illinois 60611|