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
2 other identifiers
interventional
647
1 country
1
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Feb 2011
Longer than P75 for phase_2
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
February 8, 2011
CompletedFirst Submitted
Initial submission to the registry
February 26, 2011
CompletedFirst Posted
Study publicly available on registry
March 1, 2011
CompletedPrimary Completion
Last participant's last visit for primary outcome
February 12, 2014
CompletedResults Posted
Study results publicly available
April 11, 2023
CompletedStudy Completion
Last participant's last visit for all outcomes
July 17, 2024
CompletedOctober 1, 2024
September 1, 2024
3 years
February 26, 2011
November 30, 2022
September 6, 2024
Conditions
Keywords
Outcome Measures
Primary Outcomes (3)
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
Other Outcomes (2)
Frequency of Epidermal Growth Factor Receptor (EGFR) Germline Mutations in Families With High Susceptibility to Lung Cancer
5 years
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)
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.
Study Arms (6)
A/ Erlotinib
ACTIVE COMPARATORArm A - Erlotinib 150 mg by mouth (PO) every morning (QAM)
B/ AZD6244
ACTIVE COMPARATORAZD6244 Hydrogen Sulfate 75 mg by mouth (PO) every (Q) 12 Hours
C/ MK-2206
ACTIVE COMPARATORMK-2206 200 mg by mouth (PO) every (Q) Week
D/ Lapatinib
ACTIVE COMPARATORLapatinib 1500 mg by mouth (PO) every day (QD)
E/Sunitinib
ACTIVE COMPARATORSunitinib 50 mg by mouth (PO) on days 1-28
F/ Not Otherwise Specified (NOS)
OTHERParticipants who do not meet the eligibility criteria for enrollment
Interventions
Cycle = 21 days AZD6244 Hydrogen Sulfate 75 mg by mouth (PO) every (Q) 12 Hours
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
Eligibility Criteria
You may not qualify if:
- 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 intravenous (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 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.
- 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.
- 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
- 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.
- Patients with tumor amenable to potentially curative therapy as assessed by the investigator.
- +1 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892, United States
Related Publications (5)
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.
PMID: 18390968BACKGROUNDAllen 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.
PMID: 14613031BACKGROUNDAltomare 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.
PMID: 16288292BACKGROUNDThomas 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.
PMID: 26028668DERIVEDLopez-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.
PMID: 25667274DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Dr. Arun Rajan
- Organization
- National Cancer Institute
Study Officials
- PRINCIPAL INVESTIGATOR
Arun Rajan, M.D.
National Cancer Institute (NCI)
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Investigator
Study Record Dates
First Submitted
February 26, 2011
First Posted
March 1, 2011
Study Start
February 8, 2011
Primary Completion
February 12, 2014
Study Completion
July 17, 2024
Last Updated
October 1, 2024
Results First Posted
April 11, 2023
Record last verified: 2024-09
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF
- 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.
- 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.
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).