Afatinib Genomic Landscape
|ClinicalTrials.gov Identifier: NCT02491775|
Recruitment Status : Terminated (Changes in treatment plan affecting drug therapy choices)
First Posted : July 8, 2015
Last Update Posted : March 5, 2018
|Condition or disease|
|Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer|
The current proposal will include exome and transcriptome sequencing from blood collected at baseline along with tumor samples obtained prior to starting afatinib and at the time of disease progression (a total of two tissue samples and one blood sample per patient). The samples will be collected via consent to the IRB (Institutional Review Board) approved banking study "Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma".
If carried out successfully, the proposed strategy very likely will lead to a larger and adequately powered study (perhaps using whole genome sequencing) to understand fully evolving molecular changes due to clonal selection under treatment pressure. The pace of progress in the field of sequencing technology currently underway is only likely to accelerate in the near future yielding richer and highly content-rich information. Moreover, it is likely that genomic information from DNA sequencing and transcriptome will be supplemented by analyses of translatomes and proteomes.
Successful completion of the proposed study would enable future studies to fully harness the potential of emerging technologies to develop novel approaches to treat and even ideally prevent resistance to EGFR TKIs (tyrosine-kinase inhibitor) and other molecularly targeted therapies. This could serve as a template for other cancer types as well. Over time, this approach, broadly used, would create simultaneously, highly valuable annotated tumor specimens along with germ line DNA for high-throughput genomic studies to identify novel targets and their impact on the course of disease. Re-analyzing molecular changes in the tumor at the time of disease progression would likely be a new standard of care to guide salvage therapy.
|Study Type :||Observational|
|Actual Enrollment :||6 participants|
|Official Title:||Genomic Landscape of EGFR Mutant NSCLC Prior to Afatinib and at the Time of Disease Progression Following Afatinib|
|Actual Study Start Date :||June 11, 2015|
|Actual Primary Completion Date :||February 28, 2018|
|Actual Study Completion Date :||February 28, 2018|
- Genetic changes associated with disease progression following treatment with afatinib [ Time Frame: Estimated to be 1 year ]
- The investigators will compare tumor sequencing prior to afatinib treatment to the time of disease progression to see if the genetic sequencing changed between pre-treatment and progression.
- The investigators plan to conduct exome and transcriptome sequencing of tumor before therapy with afatinib and at the time of relapse. In addition, exome sequencing of peripheral blood DNA will be done (for germline). Given the complexities of genomic analyses of paired samples in the face of limited data, the investigators will not be able to do any formal power calculations in this feasibility study.
- Disease progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
- Types of mutations in signaling kinases associated with therapeutic response [ Time Frame: Estimated to be 1 year ]
- Investigators will look at tumor tissue associated with a therapeutic response and compare with tumor tissue associated with disease progression and see if there are any mutation differences.
- Complete response is disappearance of all target lesions and non-target lesions.
- Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
- Allelic ratio of wild type to mutant EGFR (roughly corrected for intrinsic differences in tumor cellularity) with duration of response [ Time Frame: Estimated to be 1 year ]
- A variant is considered to have mutant biased expression if the variant is expressed and the variant allele frequency is greater than 20% higher in the RNA-seq data compared to the exome sequencing data. A variant is considered to have wild type biased expression if the gene is expressed, the region of the variant is covered at 5X or greater depth, and the VAF is at least 20% lower in the RNA-seq data compared to the exome sequencing data.
- Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02491775
|United States, Missouri|
|Washington University School of Medicine|
|Saint Louis, Missouri, United States, 63110|
|Principal Investigator:||Ramaswamy Govindan, M.D.||Washington University School of Medicine|