Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies
Condition: Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell Lung; Carcinoma, Thymic
MeSH terms: Carcinoma; Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma; Carcinoma, Small Cell; Thymoma
Intervention: AZD6244; MK-2206; Lapatinib; Erlotinib; Sunitinib; Molecular Profiling
Intervention description: Cycle = 21 days AZD6244 Hydrogen Sulfate 75 mg by mouth (PO) every (Q) 12 Hours; Cycle = 28 days MK-2206 200 mg by mouth (PO) every (Q) Week; Cycle = 21 days Lapatinib 1500 mg by mouth (PO) every day (QD); Cycle = 21 days Erlotinib 150 mg by mouth (PO) every morning (QAM); Cycle = 42 days Sunitinib 50 mg by mouth (PO) on days 1-28; Molecular profiling of tumor tissue. Not Otherwise Specified (NOS) arm. Participants who do not meet the eligibility criteria for enrollment or who meet eligibility criteria for a particular arm but can't be enrolled
Intervention MeSH terms: Erlotinib Hydrochloride; Sunitinib; Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 647.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: AZD6244; MK-2206; Lapatinib; Erlotinib; Sunitinib

Summary:

      Background:

      - The current standard of care for advanced lung cancer and cancers of the thymus consists
      primarily of chemotherapy treatment. The drugs used for chemotherapy depend on the
      classification of the cancer in different categories that are based on the appearance of the
      cancer in the microscope. Though this approach has been proved to be useful in some ways, the
      survival rates of individuals with lung cancer and cancers of the thymus are still very poor.
      Recent research has shown that several genetic abnormalities play an important role in the
      development and growth of lung cancer and cancers of the thymus, and that it is possible to
      improve treatment success rates with drugs that specifically target some of the abnormal
      genes. Researchers are interested in determining whether it is possible to analyze the genes
      of patients with lung cancer and cancers of the thymus in order to provide personalized
      treatment with drugs that target the specific gene abnormalities.

      Objectives:

      - To evaluate the effectiveness of genetic analysis in determining targeted therapy for
      individuals with advanced non-small cell lung cancer, small cell lung cancer, and thymic
      cancer.

      Eligibility:

      - Individuals at least 18 years of age who have been diagnosed with either lung cancer or a
      cancer of the thymus that is not considered to be curable with the use of surgery or
      radiation therapy.

      Design:

        -  Participants will be screened with a full medical history and physical examination,
           blood and urine tests, and tumor imaging studies. Participants will have a tumor biopsy
           or provide previously collected tumor tissue for study.

        -  Based on the results of the tumor biopsy study, participants will be separated into
           different treatment groups:

        -  Participants with epidermal growth factor receptor (EGFR) gene mutation will receive a
           drug called erlotinib, which inhibits a protein called EGFR that is thought to be a key
           factor in the development and progression of some cancers.

        -  Participants with Kirsten rat sarcoma virus (KRAS), proto-oncogene B-Raf (BRAF), Harvey
           Rat sarcoma virus (HRAS), or NRAF gene mutations will receive a drug called AZD6244,
           which inhibits a protein called methyl ethyl ketone (MEK) that is thought to be a key
           factor in the development and progression of some cancers.

        -  Participants with phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit
           alpha (PIK3CA), protein kinase B (AKT), or phosphatase and tensin homolog (PTEN) gene
           mutations will receive a drug called MK-2206, which inhibits a protein called AKT that
           is thought to be a key factor in the development and progression of some cancers.

        -  Participants with KIT or platelet-derived growth factor receptor A, (PDGFRA) gene
           mutations will receive a drug called sunitinib, which inhibits some proteins that are
           thought to be key factors in the development and progression of some cancers, including
           kidney cancer.

        -  Participants who have -erb-b2 avian erythroblastic leukemia viral oncogene homolog 2
           (ERBB2) gene mutation or amplification will receive a drug called lapatinib, which
           inhibits some proteins that are thought to be key factors in the development and
           progression of some cancers, including breast cancer.

        -  Participants who do not have any of the genetic abnormalities described above will be
           offered different options for treatment, including standard of care chemotherapy or
           treatment with investigational agents in a different research protocol.

        -  After 6 weeks of treatment, participants will have imaging studies to evaluate the
           status of their cancer. Treatment will continue as long as participants tolerate the
           drugs, and the disease does not progress.

        -  Participants who benefit from the first treatment but eventually develop resistance and
           progression of their cancer will be offered the chance to have a second tumor biopsy and
           undergo a different treatment for their cancer.
    

Eligibility criteria:

        -  ELIGIBILITY CRITERIA FOR INITIAL ENROLLMENT:

          -  Patients with histologically confirmed advanced Non-Small Cell Lung Cancer, (NSCLC),
             Small Cell Lung Cancer (SCLC) and thymic malignancies for whom surgical resection or
             multimodality therapy with curative intent is not feasible. For patients with Stage
             III NSCLC, who can be encompassed by a radiation port, definitive radiation therapy
             (XRT) should have been performed first when possible.

          -  Individuals who meet the eligibility criteria for epidermal growth factor receptor
             (EGFR) germline mutation testing but who do not have advanced cancer as defined in
             3.1.1 may enroll for EGFR germline mutation testing only and will not be eligible for
             the treatment or NOS arms.

          -  Patients with advanced cancer must meet one of the following criteria (does not apply
             to first degree relatives or individuals with pre-invasive histology enrolling only
             for EGFR germline mutation testing):

               -  Patients must have biopsiable disease and be willing to undergo biopsy for
                  molecular profiling

        OR

        -Patients must have enough and adequate archival material from a previous biopsy to perform
        molecular profiling analyses. The adequacy of the material provided will be determined by
        the principal investigator in conjunction with the laboratories performing the molecular
        profiling analyses

        OR

          -  Patients must have previously undergone a successful molecular profiling of their
             tumor with mutation analysis of the genes described in section 5.2, as part of this
             protocol (crossover patients) or other molecular profiling protocols such as the Lung
             Cancer Mutation Consortium protocol among others.

          -  Age greater than or equal to18 years.

        EXCLUSION CRITERIA:

          1. Patients who have had major surgery, chemotherapy or radiotherapy within 2 weeks prior
             to entering the study or those who have not recovered from adverse events due to
             agents administered more than 2 weeks earlier.

          2. Patients may not be receiving any other investigational agents or other medications
             for the treatment of their malignancy.

          3. Patients with symptomatic 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 had treatment for their brain metastases and whose brain
             metastatic disease status has remained stable for at least 1 week after the end of
             brain radiation may be enrolled to undergo molecular profiling at the discretion of
             the principal investigator. In addition, brain metastatic disease should be stable for
             at least 4 weeks, before the patients can be enrolled in any of the experimental
             treatment arms.

          4. Patients with any condition (e.g., gastrointestinal tract disease resulting in an
             inability to take oral medication or a requirement for intravenous (IV) alimentation,
             prior surgical procedures affecting absorption, or active peptic ulcer disease) that
             impairs their ability to swallow and retain tablets are excluded.

          5. Any uncontrolled medical illness that precludes the patient from undergoing a biopsy
             for molecular profiling and/or receiving treatment under one of the experimental arms
             of the study should be excluded. These conditions include but are not limited to:

               -  Ongoing or uncontrolled, symptomatic congestive heart failure (Class III or IV as
                  defined by the New York Heart Association (NYHA) functional classification system
                  (see Appendix D).

               -  Uncontrolled hypertension

               -  Unstable angina pectoris

               -  Cardiac arrhythmia

               -  Uncontrolled diabetes

               -  Uncontrolled psychiatric illness/social situations that would limit compliance
                  with study requirements.

          6. Patients with corrected QT interval (QTc) prolongation (defined as a QTc interval
             equal to or greater than 500 msec) or other significant electrocardiogram (ECG)
             abnormalities are excluded.

          7. Caution should be used if patients are required to use a concomitant medication that
             can prolong the Q wave T wave (QT) interval and efforts should be made to switch to a
             different medication before the patient begins treatment under an experimental arm.
             See Appendix E for a table of medications with the potential to prolong the QTc
             interval. A comprehensive list of agents with the potential to cause QTc prolongation
             can be found at: http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm

          8. The eligibility of patients taking medications that are potent inducers or inhibitors
             of that enzyme will be determined following a review of their case by the Principal
             Investigator. (A list of potent Cytochrome P450 3A4 (CYP3A4) inducers or inhibitors
             can be found in Appendix F). Every effort should be made to switch patients taking
             such agents or substances to other medications before they begin treatment with one of
             the experimental drug included in this protocol, particularly patients with gliomas or
             brain metastases who are taking enzyme-inducing anticonvulsant agents. A comprehensive
             list of medications and substances known or with the potential to alter the
             pharmacokinetics of sunitinib through CYP3A4 is provided in Appendix F.

          9. Patients with tumor amenable to potentially curative therapy as assessed by the
             investigator.

         10. Pregnant women are excluded from this study because many of the Food and Drug
             Administration (FDA) approved agents and investigational agents in this trial have 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 these agents, breastfeeding should be discontinued if the mother is
             treated in this protocol. These potential risks may also apply to other agents used in
             this study.