Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies

Pilot Trial of Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell Lung; Carcinoma, Thymic
• Intervention / Treatment: Drug: Erlotinib; Procedure: Molecular Profiling; Drug: AZD6244; Drug: MK-2206; Drug: Lapatinib; Drug: Sunitinib

Detailed Description

BACKGROUND:

• A better understanding of the genetic make-up of the individual tumor may offer potentially improved therapies. This approach may also give rapid access to response data in patients with sometimes rare genetic abnormalities.
• In addition, it will allow us to test targeted therapies in a select population of patients that is more likely to have a favorable response based on their molecular profile and the specific mechanism of action of the drug being tested.
• This approach will also speed up drug development and potentially approval and rescue an otherwise ineffective drug candidate for the specific subgroup that can benefit.

Primary Objectives:

• To determine the feasibility of the use of tumors molecular profiling and targeted therapies in the treatment of advanced stage non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and thymic malignancies.
• To estimate the response rate of molecular profile directed treatments in NSCLC, SCLC and thymic malignancies patients.

ELIGIBILITY:

• Patients with histologically confirmed advanced lung cancer or thymic malignancies for whom surgical resection with curative intent is not feasible.
• Patients must either have biopsiable disease and be willing to undergo biopsy for molecular profiling or have paraffin embedded tissue blocks suitable for molecular profiling analysis.
• Individuals are eligible for epidermal growth factor receptor (EGFR) germline mutation testing if they have:
• a personal history of invasive lung cancer or one of the pre-invasive histologies associated with the development of lung cancer and more than two affected family members with invasive lung cancer or one of the pre-invasive histologies associated with the development of lung cancer,

OR

• a first-degree relative with a known EGFR germline mutation (EGFR exon 20 T790M, exon 21 V843I, exon 21 R831C and exon 20 R776G).

DESIGN:

• All patients will have their tumors undergo molecular profiling. Based on these results and on other eligibility criteria, the patients will be offered enrollment into different targeted therapy arms.
• At the NCI site only, individuals eligible for EGFR germline mutation will undergo testing for germline mutations affecting the EGFR gene; if a mutation is detected, their first-degree relatives would be invited to undergo testing for the index germline mutation found in the proband and appropriate follow-up on trial.
• Effective with Amendment I, the participating site, Oregon Health and Science University (OHSU), will discontinue new enrollments and data entry for existing patients on the Not Other Specified (NOS) arm on this protocol in favor of the OHSU protocol L8639, Personalized Cancer Medicine Registry. The data from these patients will be included with the data from 11-C-0096 (8639) National Cancer Institute (NCI) patients at the time of publication. Any OHSU patients who are eligible for a treatment arm will continue to be enrolled and followed per protocol.

• Study Type: Interventional
• Enrollment (Actual): 647
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A/ Erlotinib; Arm A - Erlotinib 150 mg by mouth (PO) every morning (QAM)	Drug: Erlotinib; Cycle = 21 days Erlotinib 150 mg by mouth (PO) every morning (QAM); Other Names: Tarceva; Procedure: Molecular Profiling; 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
Active Comparator: B/ AZD6244; AZD6244 Hydrogen Sulfate 75 mg by mouth (PO) every (Q) 12 Hours	Procedure: Molecular Profiling; 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; Drug: AZD6244; Cycle = 21 days AZD6244 Hydrogen Sulfate 75 mg by mouth (PO) every (Q) 12 Hours; Other Names: Selumetinib
Active Comparator: C/ MK-2206; MK-2206 200 mg by mouth (PO) every (Q) Week	Procedure: Molecular Profiling; 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; Drug: MK-2206; Cycle = 28 days MK-2206 200 mg by mouth (PO) every (Q) Week
Active Comparator: D/ Lapatinib; Lapatinib 1500 mg by mouth (PO) every day (QD)	Procedure: Molecular Profiling; 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; Drug: Lapatinib; Cycle = 21 days Lapatinib 1500 mg by mouth (PO) every day (QD); Other Names: Tykerb
Active Comparator: E/Sunitinib; Sunitinib 50 mg by mouth (PO) on days 1-28	Procedure: Molecular Profiling; 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; Drug: Sunitinib; Cycle = 42 days Sunitinib 50 mg by mouth (PO) on days 1-28; Other Names: Sutent
Other: F/ Not Otherwise Specified (NOS); Participants who do not meet the eligibility criteria for enrollment	Procedure: Molecular Profiling; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Enrolled Participants Testing Positive for Genomic Abnormality	To determine the feasibility of the use of tumor molecular profiling and targeted therapies in the treatment of Non-Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), and Thymic Malignancies, the trial will be evaluated by determining the percentage of enrolled participants with a genomic abnormality. Identifying molecular profiles may help identify new targeted treatments for cancer.	1 year and 11 months
Number of Evaluable Participants With a Response Based on Molecular Profile Directed Treatments in Non-Small Cell Lung Cancer, (NSCLC), Small Cell Lung Cancer (SCLC), and Thymic Malignancies	Efficacy will be determined by assessing if participants who have treatment assigned on the basis of their molecular profiling results will exhibit reasonable response to the drug selected for their particular profile. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study Progressive Disease (PD) 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 is the smallest on study). The appearance of one or more new lesions is also considered progressions.	1 year and 13 months
Percentage of Evaluable Participants Overall Response Rate (ORR) Based on the Drug Selected for Their Particular Profile	Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).Partial Response (PD) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study Progressive Disease (PD) 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 is the smallest on study). The appearance of one or more new lesions is also considered progressions.	1 year and 13 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Epidermal Growth Factor Receptor (EGFR) Germline Mutations in Families With High Susceptibility to Lung Cancer	The frequency of EGFR germline mutations will be determined by enrolling participants from families with high susceptibility to lung cancer and their first-degree relatives (at the National Cancer Institute (NCI) site only).	5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Here is the Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Date treatment consent signed to date off study, approximately 122 months and 25 days, 88 months and 16 days, and 126 months and 2 days for each group respectively.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Arun Rajan, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Allen LF, Sebolt-Leopold J, Meyer MB. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol. 2003 Oct;30(5 Suppl 16):105-16. doi: 10.1053/j.seminoncol.2003.08.012.
• Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, Hanson LJ, Gore L, Chow L, Leong S, Maloney L, Gordon G, Simmons H, Marlow A, Litwiler K, Brown S, Poch G, Kane K, Haney J, Eckhardt SG. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008 May 1;26(13):2139-46. doi: 10.1200/JCO.2007.14.4956. Epub 2008 Apr 7.
• Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005 Nov 14;24(50):7455-64. doi: 10.1038/sj.onc.1209085.
• Thomas A, Chen Y, Steinberg SM, Luo J, Pack S, Raffeld M, Abdullaev Z, Alewine C, Rajan A, Giaccone G, Pastan I, Miettinen M, Hassan R. High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis. Oncotarget. 2015 May 10;6(13):11694-703. doi: 10.18632/oncotarget.3429.
• Lopez-Chavez A, Thomas A, Rajan A, Raffeld M, Morrow B, Kelly R, Carter CA, Guha U, Killian K, Lau CC, Abdullaev Z, Xi L, Pack S, Meltzer PS, Corless CL, Sandler A, Beadling C, Warrick A, Liewehr DJ, Steinberg SM, Berman A, Doyle A, Szabo E, Wang Y, Giaccone G. Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol. 2015 Mar 20;33(9):1000-7. doi: 10.1200/JCO.2014.58.2007. Epub 2015 Feb 9.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2011
• Primary Completion (Actual): February 12, 2014
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: February 26, 2011
• First Submitted That Met QC Criteria: February 26, 2011
• First Posted (Estimated): March 1, 2011

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Erlotinib; Lapatinib; Sunitinib; AZD6244; MK-2206
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphatic Diseases; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Neoplasms, Complex and Mixed; Thymus Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Thymoma; Small Cell Lung Carcinoma; Carcinoma, Small Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Erlotinib Hydrochloride; Sunitinib; Lapatinib
• Other Study ID Numbers: 110096; 11-C-0096

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study PI. Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No