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...

Study Overview
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Brief Summary
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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
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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.

Official Title
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Randomized Phase II Study of AZD6244 MEK-Inhibitor With Erlotinib in KRAS Wild Type and KRAS Mutant Advanced Non-Small Cell Lung Cancer

Conditions
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Non Small Cell Lung Carcinoma

Intervention / Treatment
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* Drug: AZD6244
* Drug: Erlotinib
* Drug: AZD6244 + Erlotinib


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have histologically or cytologically confirmed advanced (Stage IV) Non Small Cell Lung Cancer that has been verified by the enrolling institution s pathology department. Mixed histologies, with small cell lung cancer components are not eligible. Patients must have measurable disease by RECIST criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT (computed tomography) scan. Patients must have had at least one prior platinum-containing chemotherapy regimen, or have refused cytotoxic chemotherapy. Patients should have no more than two prior chemotherapy regimens. Chemotherapy regimens have no limit on the maximum or minimum number of cycles. Patients enrolled on the trial should have completed their last chemotherapy regimen at least 4 weeks ago. Patients should have completed radiation therapy at least 4 weeks prior to enrollment. Adjuvant and neoadjuvant chemotherapy does not count as prior chemotherapy for advanced disease if more than a year before enrollment. Age greater than or equal to 18 years, because no dosing or adverse event data are currently available on the use of AZD6244 (ARRY-142886) as monotherapy or in combination with erlotinib in patients less than 18 years of age. Children are excluded from this study but will be eligible for future pediatric phase 2 combination trials. Life expectancy of greater than 3 months. ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%). Patients must have normal organ and marrow function as defined below: leukocytes greater than or equal to 3,000/mcL absolute neutrophil count greater than or equal to 1,500/mcL platelets greater than or equal to 100,000/mcL total bilirubin within normal institutional limits AST (aspartate aminotransferase) (SGOT (serum glutamic oxaloacetic transaminase)) /ALT (alanine aminotransferase) ((SGPT (serum glutamic pyruvic transaminase)) less than or equal to 2.5 X institutional upper limit of normal creatinine within normal institutional limits OR creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Patients must have adequate archival material from a previous biopsy to determine KRAS status at the time of enrollment, or undergo a biopsy of fresh tissue of the primary cancer lesion or a metastatic site in order to make this determination. The effects of AZD6244 and erlotinib on the developing human fetus at the recommended therapeutic dose are unknown. However preclinical data showing adverse effects on fetal survival and development with AZD6244 have been reported. For this reason since there is a potential risk of teratogenicity, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for four weeks after dosing with AZD6244 ceases. Women of child-bearing potential must have a negative pregnancy test prior to entry. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Please note that the AZD6244 manufacturer recommends that adequate contraception for male patients should be used for 16 weeks post-last dose due to sperm life cycle. Ability to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered to less than or equal to grade 1 toxicities from adverse events due to agents administered more than 4 weeks earlier. Patients may not be receiving any other investigational agents. In general, patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, patients who have completed primary treatment of their brain metastasis by surgery or radiotherapy and have been off steroids (with the exception of maintenance replacement steroids) and anti-seizure medications for greater than one month without progression of neurological symptoms are eligible for enrollment in this trial. Stability of treated brain metastases should be confirmed by repeat imaging studies (CT brain or MRI (magnetic resonance imaging) brain) performed at least one month after completion of treatment. Previous MEK (methyl ethyl ketone) inhibitor or prior treatment with EGFR TKI (tyrosine kinase inhibitor). Major surgery or significant traumatic injury occurring within 21 days prior to treatment. Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogrens syndrome), congenital abnormality (e.g., Fuchs dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test). Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV (intravenous) alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease. Patients with uncontrolled hypertension already on optimal medication, patients with class II or greater heart failure, any current or prior history of cardiomyopathy. Patient with baseline LVEF (left ventricular ejection fraction) less than 50%, atrial fibrillation, recent myocardial infarction, or unstable ischemic heart disease. Patients with QTc (corrected QT interval) interval greater than 450 msecs or other factors that increase the risk of QT (Q wave, T wave) prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that meets New York Heart Association (NYHA) class III and IV definitions are excluded. This does not include QTc prolongation secondary to a paced rhythm. If a patient has a paced rhythm, QTc levels less than or equal to 500 (Grade 1) are allowed and patients with QTc > 500 are excluded. Required use of a concomitant medication that can prolong the QT interval. A comprehensive list of agents with the potential to cause QTc prolongation can be found at http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, Hepatitis B or C, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because AZD6244 is a MEK- Inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD6244, breastfeeding should be discontinued if the mother is treated with AZD6244. These potential risks may also apply to other agents used in this study. HIV (human immunodeficiency virus) -positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD6244. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. INCLUSION OF WOMEN AND MINORITIES: Both men and women and members of all races and ethnic groups are eligible for this trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: KRAS Mut 2<br>KRAS Mutant patients randomized to combination therapy arm | Drug: AZD6244 + Erlotinib<br>* For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erl (erlotinib) mg qd.<br>|
| Active Comparator: KRAS Mut 1<br>KRAS Mutant patients randomized to monotherapy arm | Drug: AZD6244<br>* For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).<br>|
| Active Comparator: WT KRAS 1<br>Wild-Type KRAS patients randomized to monotherapy arm | Drug: Erlotinib<br>* For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd (every day)<br>|
| Active Comparator: WT KRAS 2<br>Wild-Type KRAS patients randomized to combination therapy arm | Drug: AZD6244 + Erlotinib<br>* For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erl (erlotinib) mg qd.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | 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). | 2.1 to 4 months | 
| Objective Response | 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. | Up to 37 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module. | 42 months | 
| Percentage of Participants With Disease Control/Stabilization | 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. | 3 cycles or up to 84 days | 
| Overall Survival | Time between the first day of treatment to the time of death. | Up to 26 months | 
| Percentage of Th17 in Cluster of Differentiation 4 (CD4)+T Cells at Baseline in Relation to Response | 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. | Pretreatment - Cycle 1 Day 1 | 
| Number of Participants With a Reduction in Phosphorylated Extracellular Signal-Regulated Kinases (p-ERK) in Lymphocytes | 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. | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kinase Signal Transduction Pathway, Tumor Mutational Analysis, Tissue Immunohistochemistry, MIB-1 (Ki-67) Rate, PERK Level, Lung Cancer, Non-Small Cell Lung Cancer