Non Small Cell Lung Carcinoma Clinical Trial
Official title:
Randomized Phase II Study of AZD6244 MEK-Inhibitor With Erlotinib in KRAS Wild Type and KRAS Mutant Advanced Non-Small Cell Lung Cancer
Background:
AZD6244 (ARRY-142886) is an investigational anticancer drug that is designed to block a
critical component (MEK (methyl ethyl ketone)) of a pathway (MAP (mitogen-activated protein)
kinase pathway) that causes some lung cancer cells to grow. The MAP kinase pathway could be
overactive in a proportion of lung cancers, including some which also have another mutation
in a protein known as KRAS (Kirsten rat sarcoma viral oncogene homolog). Approximately 20%
of lung cancers have KRAS mutations which can make some cancer treatments including
erlotinib, a standard anticancer treatment drug less effective. Researchers are interested
in determining whether AZD6244 is effective in treating advanced NSCLC (non small cell lung
cancer), including KRAS mutated lung cancer that has not responded to standard therapy.
Objectives:
To determine the effectiveness of AZD6244, either alone or in combination with erlotinib, in
preventing tumor growth in individuals with NSCLC.
Eligibility:
Individuals at least 18 years of age who have been diagnosed with advanced NSCLC that has
not responded to standard therapy.
Design:
- Participants will be screened with a medical history, physical examination, blood
tests, imaging studies, and potentially, tumor biopsy tests to determine whether a
participant's NSCLC contains mutations in the KRAS protein.
- Participants will be divided into two groups based on the status of the KRAS protein in
their NSCLC tumor cells:
- Individuals with normal KRAS protein: Half will receive AZD6244 and erlotinib, and half
will receive only erlotinib.
- Individuals with mutated KRAS protein: Half will receive AZD6244 and erlotinib, and
half will receive only AZD6244.
- Participants will take their assigned medications daily (on an empty stomach in the
morning and/or evening, depending on the treatment) for 28-day cycles of treatment.
Participants will also keep a medication diary to record any side effects.
- Participants will have frequent blood tests during the first cycle of treatment, and
will have imaging studies or other tests as required by the study researchers.
Participants may also have an additional tumor biopsy after the end of the first
treatment cycle.
- Treatment will continue until the disease progresses, significant side effects develop,
the participant chooses to leave the study, or the researchers end the study....
Background:
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
(epidermal growth factor receptor) tyrosine kinase inhibitor. Several mechanisms of
resistance to EGFR tyrosine kinase inhibitors have been discovered. Presence of KRAS
mutations is one of them. AZD6244 (ARRY-142886) 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.
Objectives:
- 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 (partial response) + CR (complete response))
either monotherapy AZD6244 or the combination AZD6244 plus erlotinib in patients with
mutated KRAS advanced NSCLC
- Evaluate disease control rate (PR+CR+SD (stable disease)) 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
response.
- Measure changes in a tumors MIB-1 (Ki-67) rate and pERK levels in response to treatment
with AZD6244.
Eligibility:
- 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 (Response Evaluation Criteria in Solid Tumors) criteria.
- Adequate renal, cardiac, hepatic and hematopoietic functions
- No major surgery, radiotherapy, or chemotherapy within 28 days of enrollment.
Design:
- 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 (Common Terminology Criteria for
Adverse Events) Version 4.0.
- Tumor assessments by RECIST 1.1 criteria will be performed every 2 cycles (one cycle is
28 days).
- 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
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