Sponsored by National Institutes of Health Clinical Center (CC)

Phase	Quota	Distance
Phase 2		Near

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 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 KRAS, BRAF, HRAS, or NRAF gene mutations will receive a drug called AZD6244, which inhibits a protein called MEK that is thought to be a key factor in the development and progression of some cancers.
• Participants with PIK3CA, AKT, or 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 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 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.

Study Start Date: January 2011

Estimated Completion Date: January 2017

Specialties: Pulmonology: Clinical Pharmacology,Lung/Thoracic Oncology Oncology: Lung/Thoracic Oncology,Pharmacology/Therapy

Interventions

• Drug: MK-2206
• Drug: Sunitinib
• Drug: AZD6244
• Procedure: Molecular Profiling
• Drug: Lapatinib
• Drug: Erlotinib
• Drug: AZD

Inclusion criteria

ELIGIBILITY CRITERIA FOR INITIAL ENROLLMENT:

• Patients with histologically confirmed advanced NSCLC, 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 XRT should have been performed first when possible.
• Individuals who meet the eligibility criteria for 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 firstdegree 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.

ELIGIBILITY CRITERIA FOR ENROLLMENT INTO THE TREATMENT ARMS

 

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan. -Target lesions cannot be selected within previously irradiated areas, if not newly arising or clearly progressing after irradiation as proven by repeat scanning.
• Life expectancy of greater than 3 months.
• Performance status (ECOG) <= 2 (See Appendix C).
• Patients must have normal organ and marrow function as defined below:
• leukocytes: > 1,500/mcL
• absolute neutrophil count: > 1,000/mcL
• platelets: > 100,000/mcL
• total bilirubin*: < 1.5 times the institutional upper limit of normal--For patients with Gilbert's syndrome or levels of indirect bilirubin above the upper limit of normal, direct bilirubin will be used for eligibility and should be < 1.5 times the institutional upper limit of normal.
• AST(SGOT)/ALT(SGPT): less than 3 times the institutional upper limit of normal
• Creatinine: less than or equal to1.5 times the institutional upper limits of normal

 

OR creatinine clearance > 50 mL/min/1.73 m(2) for patients with creatinine levels above 1.5 times the institutional normal.

• Patients must have recovered from toxicity related to prior therapy (chemotherapy, surgery or radiation) to grade <= 1 (defined by CTCAE: The NCI Common Terminology Criteria for Adverse Events Version 4(CTCAE) will be used for toxicity and adverse event reporting. All appropriate treatment areas have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov).
• The effects of most of the therapeutic agents used in this trial on the developing human fetus at the recommended therapeutic doses are unknown. For this reason and because some agents are known to be teratogenic, 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 continue for at least 16 weeks after completing the study to avoid pregnancy and/or potential adverse effects on the developing embryo. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with targeted therapies, breastfeeding should be discontinued if the mother is treated with targeted therapies.
• Ability to understand and the willingness to sign a written informed consent document.

SPECIFIC ELIGIBILITY CRITERIA FOR ENROLLMENT IN TREATMENT ARMS

The following is a description of the eligibility criteria required to be enrolled in the specific molecular profile based treatment arms of this study which include: Erlotinib, AZD6244, MK-2206, Lapatinib and Sunitinib arms. This is in addition to the general eligibility and exclusion criteria.

ERLOTINIB ARM

• Patients must have an EGFR TKI sensitizing mutation as determined by analysis of the primary tumor or a metastatic site in a CLIA certified laboratory.
• Patients with SCLC or thymic malignancies must have been treated with at least 1 previous standard of care chemotherapy regimen or refuse to be treated with conventional chemotherapy agents.

AZD6244 ARM

 

• Patients must have one of the following as determined by analysis of the primary tumor or a metastatic site in a CLIA certified laboratory:
• KRAS mutation or
• NRAS mutation or
• HRAS mutation or
• BRAF mutation
• Patients must have been treated with at least 1 previous standard of care chemotherapy regimen or refuse to be treated with conventional chemotherapy agents.

MK2206 ARM

 

• Patients must have one of the following as determined by analysis of the primary tumor or a metastatic site in a CLIA certified laboratory:
• PI3KCA mutation or
• PI3KCA gene amplification by FISH (gene to chromosome ration > 2) or
• AKT mutation or
• PTEN mutation
• Patients must have been treated with at least 1 previous standard of care chemotherapy regimen or refuse to be treated with conventional chemotherapy agents.

LAPATINIB ARM

 

• Patients must have one of the following as determined by analysis of the primary tumor or a metastatic site in a CLIA certified laboratory:
• ERBB2 mutation or
• ERBB2 gene amplification by FISH (gene to chromosome ration > 2)
• Patients must have been treated with at least 1 previous standard of care chemotherapy regimen or refuse to be treated with conventional chemotherapy agents.

SUNITINIB ARM

 

• Patients must have one of the following as determined by analysis of the primary tumor or a metastatic site in a CLIA certified laboratory:
• PDGFR-A mutation or
• PDGFR-A gene amplification by FISH (gene to chromosome ration > 2) or
• KIT mutation
• Patients must have been treated with at least 1 previous standard of care chemotherapy regimen or refuse to be treated with conventional chemotherapy agents.

Exclusion criteria

EXCLUSION CRITERIA FOR ENROLLMENT INTO THE TREATMENT ARMS

• 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.
• Patients may not be receiving any other investigational agents or other medications for the treatment of their malignancy.
• 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.
• Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain tablets are excluded.
• 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 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.
• Patients with QTc prolongation (defined as a QTc interval equal to or greater than 500 msec) or other significant ECG abnormalities are excluded.
• Caution should be used if patients are required to use a concomitant medication that can prolong the 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
• 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 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.
• Patients with tumor amenable to potentially curative therapy as assessed by the investigator.
• Pregnant women are excluded from this study because many of the 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.

SPECIFIC EXCLUSION CRITERIA FOR ENROLLMENT IN TREATMENT ARMS

ERLOTINIB ARM

• Previous anti-EGFR TKI therapy
• Patients with a known EGFR TKI resistant mutation.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Erlotinib.

AZD6244 ARM

• Any prior exposure to MEK, Ras, or Raf inhibitors .
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244.
• Cardiac conditions as follows:
• Uncontrolled hypertension (BP greater than or equal to 150/95 despite optimal therapy)
• Heart failure NYHA Class II or above (See Appendix D)
• Prior or current cardiomyopathy
• Baseline LVEF less than or equal to 50%.
• Atrial fibrillation with heart rate > 100 bpm
• Unstable ischaemic heart disease (MI within 6 months prior to starting treatment, or angina requiring use of nitrates more than once weekly).
• Laboratory values as listed below (SI units):
• Absolute Neutrophil Count (ANC) < 1.5x109/L (1500 per mm(3))
• Platelets < 100x109/L (100,000 per mm(3))
• Hemoglobin (Hgb) < 9.0 g/dL
• Serum bilirubin > 1.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST/SGOT) or alanine aminotransferase (ALT/SGPT) > 2.5 times the ULN (greater than or equal to 5 ULN in presence of liver metastases).

MK2206 ARM

• Previous AKT inhibitor therapy.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206.
• Preclinical studies demonstrated the potential of MK-2206 for induction of hyperglycemia in all preclinical species tested. Patients with diabetes or in risk for hyperglycemia should not be excluded from trials with MK-2206, but the hyperglycemia should be well controlled on oral agents before the patient enters the trial.

LAPATINIB ARM

• Previous Lapatinib therapy.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib.
• LVEF < 50%

SUNITINIB ARM

• Previous sunitinib therapy
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib.
• Patients who require use of therapeutic doses of coumarin-derivative anticoagulants such as warfarin are excluded. Note: Low molecular weight heparin is permitted provided the patient's PT INR is < 1.5.
• Patients with any of the following conditions are excluded:
• Serious or non-healing wound, ulcer, or bone fracture.
• History of abdominal fistula

Study Locations And Contact Information

• Oregon Health Sciences University Cancer Center, Portland Oregon
  
• National Institutes of Health Clinical Center 9000 Rockville Pike, Bethesda Maryland
  
• Oregon Health Sciences University Cancer Center, Portland Oregon