Afatinib Genomic Landscape

ID: NCT02491775
Status: Recruiting
Phase: N/A
Start Date: June 11, 2015
First Submitted: June 15, 2015
Last Updated: February 22, 2018
Results: N/A
Sponsors & Collaborators: Washington University School of Medicine, Boehringer Ingelheim
Location: United States
Conditions: Carcinoma, Non-Small-Cell Lung, Non-Small Cell Lung Cancer, Non-small Lung Cancer
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Study Description

Brief Summary

The investigators propose to conduct a pilot feasibility study of single agent afatinib in patients with previously untreated metastatic EGFR (epidermal growth factor receptor) mutant adenocarcinoma of the lung (NSCLC = non-small cell lung cancer) with the sole purpose of characterizing the genomic landscape before afatinib and at the time of disease progression.

Detailed Description

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.
Condition or disease Intervention/treatment Phase

Carcinoma, Non-Small-Cell Lung

Non-Small Cell Lung Cancer

Non-small Lung Cancer

N/A

Tracking Information

First Submitted DateJune 15, 2015
Last Update Posted DateFebruary 22, 2018
Actual Start DateJune 11, 2015
Anticipated Completion DateJanuary 31, 2019
Actual Primary Completion DateJanuary 31, 2019
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • 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.

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • 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. Therapeutic Response 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).

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleAfatinib Genomic Landscape
Official TitleGenomic Landscape of EGFR Mutant NSCLC Prior to Afatinib and at the Time of Disease Progression Following Afatinib
Brief Summary

The investigators propose to conduct a pilot feasibility study of single agent afatinib in patients with previously untreated metastatic EGFR (epidermal growth factor receptor) mutant adenocarcinoma of the lung (NSCLC = non-small cell lung cancer) with the sole purpose of characterizing the genomic landscape before afatinib and at the time of disease progression.

Detailed Description

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 TypeObservational
Study PhaseN/A
Estimated Enrollment
30
Allocation
Not Available
Interventional Model
Not Available
Masking
Not Available
Primary Purpose
Not Available
Conditions
Carcinoma, Non-Small-Cell Lung
Non-Small Cell Lung Cancer
Non-small Lung Cancer
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodNon-Probability Sample
Study PopulationParticipants will be selected from the Washington University School of Medicine and Barnes-Jewish healthcare system who previously consented to study HRPO (Human Research Protection Office)# 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma").
Intervention
Not Available
Study Groups/Cohorts
Not Available
Study Arms
Not Available
Arm Intervention/Treatment

Recruitment Information

Recruitment Status:Recruiting
Enrollment30
Completion DateJanuary 31, 2019
Eligibility Criteria: Inclusion Criteria/
Exclusion Criteria:
- Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma
- Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R)
- Absence of known resistant mutations in the EGFR TK domain (T790M)
- Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma")
- No prior treatment for this malignancy
- No prior localized therapy to the biopsy site
- Planned treatment with standard of care afatinib at 40 mg QD (daily)
- Not pregnant or breastfeeding
- At least 18 years of age
GenderAll
Age18 Years to N/A
Accepts Healthy VolunteersNo
Contacts
Listed Location Countries
United States

Administrative Information

NCT Number:NCT02491775
Other Study ID Numbers
201408008
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
Washington University School of Medicine
Collaborators
Boehringer Ingelheim
Investigators
Principal Investigator
Ramaswamy Govindan, M.D.
Washington University School of Medicine