Randomized Phase II Study of AZD6244 MEK-Inhibitor With Erlotinib in KRAS Wild Type and KRAS Mutant Advanced Non-Small Cell Lung Cancer
Lung Cancer is the leading cause of death among both men and women. Of the approximately
172,000 patients that are diagnosed every year with non small cell lung cancer (NSCLC) in
the US, 55% present with advanced stage disease. The current treatment for advanced NSCLC is
first line chemotherapy with a platinum-based doublet. Second line treatment for recurrent
or progressive disease includes treatment with chemotherapy or treatment with an oral EGFR
tyrosine kinase inhibitor. Several mechanisms of resistance to EGFR tyrosine kinase
inhibitors have been discovered. Presence of KRAS mutations is one of them. AZD6244 is an
investigational drug that is orally available and targets the critical kinase (MEK) in the
mitogen-activated protein (MAP) kinase signal transduction pathway which is activated in
NSCLC and is downstream of EGFR.
- Determine the progression free survival (PFS) using the combination of AZD6244 and
erlotinib in patients with wild type KRAS advanced NSCLC
- Determine the clinical response rate (PR+CR) either monotherapy AZD6244 or the
combination AZD6244 plus erlotinib in patients with mutated KRAS advanced NSCLC
- Evaluate disease control rate (PR+CR+SD) and overall survival in both patient groups.
- Determine a safety profile for use of AZD6244 in combination with erlotinib in patients
with advanced NSCLC.
- Measure serological markers to evaluate if these markers are correlated with tumor
- Measure changes in a tumor's MIB-1 (Ki-67) rate and pERK levels in response to
treatment with AZD6244.
- Patients with pathologically confirmed NSCLC not amenable to potentially curative
therapy and having progressed after being treated with at least one prior platinum
containing chemotherapy regimen, or having refused cytotoxic chemotherapy.
- Progressive disease should be documented prior to enrollment on the study.
- Patient should not have more than 2 prior chemotherapy regimens.
- Measurable disease by RECIST criteria.
- Adequate renal, cardiac, hepatic and hematopoietic functions
- No major surgery, radiotherapy, or chemotherapy within 28 days of enrollment.
- Patients will be stratified on the basis on their KRAS mutational status. Wild-Type
KRAS patients will be randomized to receive either single agent erlotinib 150 mg/day or
the combination of erlotinib 100 mg/day plus AZD6244 at 150 mg/day. KRAS mutant
patients will be randomized to receive AZD6244 monotherapy at a dose of 75 mg twice per
day, or the combination AZD6244 at 150 mg/day plus erlotinib 100 mg/day.
- Treatment will continue until disease progression.
- Toxicity will be assessed every cycle by the CTCAE Version 4.0.
- Tumor assessments by RECIST 1.1 criteria will be performed every 2 cycles (one cycle is
- Correlative studies including initial tumor mutational analysis and tissue
immunohistochemistry (IHC) studies will be done on existing tumor blocks, or
re-biopsied tissue prior to enrollment.
- Patients will be evaluated for the potential to undergo repeat tumor biopsy after 1
cycle of therapy. Tumors will be assessed for MIB-1 (Ki-67) and pERK levels by IHC.
- The study will accrue up to 40 patients with wild-type KRAS NSCLC and up to 60 patients
with mutated KRAS NSCLC.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
1) Progression free survival using AZD6244 + erlotinib in wild type KRAS advanced NSCLC; and 2) Clinical response rate using AZD6244 monotherapy or AZD6244 + erlotinib combination therapy in KRAS mutant advanced NSCLC
Arun Rajan, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|City of Hope Medical Group||Pasadena, California 91105|
|University of Chicago Medical Center||Chicago, Illinois 60637|
|University of California, Davis||Sacramento, California 95818|