Tarceva and AT-101 for Patients With Advanced Non-Small Cell Lung Cancer
The purpose of this study the safety and effectiveness of oral AT-101 when given with the standard dose of erlotinib (Tarceva)to patients who are older that 18 and who have advanced non-small cell lung cancer, who have relapsed or progressed on prior platinum-based chemotherapy.
It is proposed that the effects of AT-101 may improve the clinical benefit of erlotinib in patients with advanced NSCLC.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study of Erlotinib (Tarceva) in Combination With AT-101 in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)|
- To determine the safety and tolerability of erlotinib plus AT-101 [ Time Frame: Assessment of toxicity will be performed on day 15 of the first cycle, and then on day 1 of every cycle of treatment. ] [ Designated as safety issue: Yes ]
- Evaluation of efficacy for erlotinib plus AT-101 using the binary outcome "alive without progression at 6 months (AWOP6)" as a secondary endpoint. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
|Study Start Date:||February 2010|
|Estimated Study Completion Date:||June 2015|
|Estimated Primary Completion Date:||January 2011 (Final data collection date for primary outcome measure)|
Experimental: AT-101 plus Erlotinib
Subjects will begin study treatment at 150 mg of erlotinib taken once daily in a continuous regimen expressed in 3 week cycles.
Subjects will begin treatment with oral AT-101 at 40 mg twice daily for 3 days of each 3 week cycle on an outpatient basis.
Drug: Tarceva plus AT-101
150 mg of Tarceva taken once daily in a continuous regimen expressed in 3 week cycles.
Oral AT-101 at 40 mg twice daily for 3 days of each 3 week cycle on an outpatient basis.
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.