Phase I Study of Erlotinib (Tarceva) in Combination With AT-101 in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is the leading cause of death in the United States as well as worldwide. It is
estimated that approximately 215,020 new cases of lung cancer will be diagnosed in the
United States in 2008, with approximately 161,840 deaths (1). The great majority of the
lung cancers are grouped as non small cell lung cancer (NSCLC), and only 13% as small cell
lung cancer. Most patients with NSCLC present with advanced disease (55% with stage IIIB or
IV). The overall median survival of patients with advanced NSCLC treated with first line
platinum based doublets is less than 12 months (8 10 months) with a 1 year and 2 year
survival of 33% and 11%, respectively (2-4). Agents targeting epidermal growth factor
receptor (EGFR), matrix metalloproteinase, farnesyl transferase, protein kinase C and
retinoic X receptor have so far shown no survival benefit in combination with chemotherapy
in advanced NSCLC (5-10).
More recently, 2 trials have shown clinical evidence of anti tumor activity with the
addition of bevacizumab to first line chemotherapy in patients with advanced NSCLC (11,12).
The pivotal study (EGOC 4599) responsible for the approval of bevacizumab in combination
with carboplatin plus paclitaxel in selective patients with advanced non squamous cell lung
cancers demonstrated a 2 month improvement in the median survival (12.3 months versus 10.3
months), and a higher objective response rate (12).
Patients with disease progression on or after first line therapy may be candidates for
second line chemotherapy with either docetaxel or pemetrexed, which results in a modest
improvement in survival. More recently, 2 EGFR tyrosine kinase inhibitors (TKIs), gefitinib
and erlotinib, have been approved for second and third line therapy in advanced NSCLC
(13,14). The effect on overall survival in genotypically uncharacterized patients was
observed with erlotinib (BR21 trial), but not with gefitinib (ISEL trial), contributing to
the withdrawal of gefitinib from the United States, and the approval of erlotinib as second
and third line therapy in NSCLC irrespective of tumor genotype (15).
It is proposed that the effects of AT-101 on the downstream signaling pathways of the EGFR,
particularly inhibition of the anti-apoptotic members Bcl-2 family of proteins, may provide
an opportunity to improve the clinical benefit of erlotinib in patients with advanced NSCLC.
The safety of the combination of erlotinib with AT-101 has not been assessed. It is
therefore proposed that a phase I study be performed using standard (FDA approved) dose of
erlotinib (150 mg/day) with an effective dose of AT-101 (40 mg twice daily for 3 days) of a
3 week cycle.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the safety and tolerability of erlotinib plus AT-101
Assessment of toxicity will be performed on day 15 of the first cycle, and then on day 1 of every cycle of treatment.
Francisco Robert, M.D.
University of Alabama at Birmingham
United States: Food and Drug Administration