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...
Condition: Non Small Cell Lung Carcinoma
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: AZD6244; Erlotinib; AZD6244 + Erlotinib
Intervention description: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).; For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd (every day); 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.
Intervention MeSH terms: Erlotinib Hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 89.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Kinase Signal Transduction Pathway; Tumor Mutational Analysis; Tissue Immunohistochemistry; MIB-1 (Ki-67) Rate; PERK Level; Lung Cancer; Non-Small Cell Lung Cancer

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....
    

Eligibility criteria:

        -  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.