Randomized Phase II Study of AZD6244 (Mitogen-activated Protein Kinase Inhibitor) MEK-Inhibitor With Erlotinib in KRAS Wild Type Advanced Non-Small Cell Lung Cancer (NSCLC) and a Randomized Phase II Study of AZD6244 With Erlotinib in Mutant KRAS Adva...
- Conditions
- Non Small Cell Lung Carcinoma
- Interventions
- Registration Number
- NCT01229150
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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....
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 89
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description WT KRAS 2 AZD6244 + Erlotinib Wild-Type KRAS patients randomized to combination therapy arm KRAS Mut 1 AZD6244 KRAS Mutant patients randomized to monotherapy arm KRAS Mut 2 AZD6244 + Erlotinib KRAS Mutant patients randomized to combination therapy arm WT KRAS 1 Erlotinib Wild-Type KRAS patients randomized to monotherapy arm
- Primary Outcome Measures
Name Time Method Progression Free Survival 2.1 to 4 months Time between the first day of treatment to the day of disease progression. Progressive disease is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that's the smallest on study). In addition to the relative increase of 20% of at least 5mm. (Note: the appearance of one or more lesions is also considered progression).
Objective Response Up to 37 months Objective response is complete response + partial response. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
- Secondary Outcome Measures
Name Time Method Number of Participants With Adverse Events 42 months Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Overall Survival Up to 26 months Time between the first day of treatment to the time of death.
Percentage of Th17 in Cluster of Differentiation 4 (CD4)+T Cells at Baseline in Relation to Response Pretreatment - Cycle 1 Day 1 First the number of T cells that are CD4+ is determined by staining with an antibody to CD4 and measured in a flow cytometer. Then the number of Th17+ cells is determined by staining with an antibody to IL-17 and measured in a flow cytometer. Then the percentage of CD4+ cells that are also Th17 cells is determined as a simple ratio, i.e. Th17cells/CD4 cells. This ratio is reported here for each category of KRAS mutation status for whom we had patients.
Percentage of Participants With Disease Control/Stabilization 3 cycles or up to 84 days Disease control/stabilization is the percentage of participants with partial response (PR) + complete response (CR) + stable disease (SD). Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progressions.), taking as reference the smallest sum diameters.
Number of Participants With a Reduction in Phosphorylated Extracellular Signal-Regulated Kinases (p-ERK) in Lymphocytes Cycle 1 Day 1 pre-treatment with Cycle 1 Day 2 (1 day after starting treatment), and Cycle 1 Day 14 (2 weeks after starting treatment) Level of p-ERK was measured by the median channel cumber of fluorescence intensity. Data are relative to the level before therapy begins(C1D1).Then we see what the level was after therapy \& compare. Every value after therapy is compared to pre-therapy, \& every patient is their own control. To do that, we make C1D1 equal to 1 for every patient \& then compare the pERK level after therapy by looking at the fold change in pERK level.
Trial Locations
- Locations (5)
University of Southern California Health Sciences Campus
🇺🇸Los Angeles, California, United States
City of Hope Medical Group
🇺🇸South Pasadena, California, United States
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
University of California, Davis
🇺🇸Davis, California, United States
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States