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Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer

NCT02151721 · Status: UNKNOWN · Phase: PHASE1 · Type: INTERVENTIONAL · Enrollment: 12

Last updated 2018-02-05

No results posted yet for this study

Summary

* Gefitinib is an orally active epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). However, 20-30% of patients with EGFR-activating mutations show intrinsic resistance to EGFR-TKI.
* EGFR-mutant non-small cell lung cancer (NSCLC) cells with BIM (BCL2L11) deletion polymorphism show the impaired generation of BIM with the proapoptotic BH3 domain, as well as resistance to EGFR-TKI-induced apoptosis.
* Both BIM polymorphism (12.9%) and EGFR mutations (50% in lung adenocarcinoma) are more prevalent in the East Asian than in Caucasian populations. BIM is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGFR-TKI in EGFR-mutant NSCLC.
* Vorinostat (suberoylanilide hydroxamic acid \[SAHA\]) is a small-molecule inhibitor of histone deacetylase (HDAC) and induces cell differentiation, cell cycle arrest, and apoptosis in several tumor cells. HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in patients with EGFR-mutant NSCLC in whom resistance to EGFR-TKI is associated with a common BIM polymorphism. EGFR-TKI resistance due to the BIM polymorphism may be able to be circumvented in combination with HDAC inhibition of vorinostat with gefitinib in NSCLC.

Conditions

  • Non-Small-Cell Lung Carcinoma

Interventions

DRUG

Vorinostat, gefitinib

Vorinostat 200, 300, or 400 mg orally once daily on days 1-7 with washout on days 8-14 plus gefitinib 250 mg orally once daily on days 1-14

Sponsors & Collaborators

  • Kanazawa University

    lead OTHER

Principal Investigators

  • Seiji Yano, MD, PhD · Kanazawa University Hospital

Study Design

Allocation
NA
Purpose
TREATMENT
Masking
NONE
Model
SINGLE_GROUP

Eligibility

Min Age
20 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2014-06-01
Primary Completion
2018-02-20
Completion
2018-02-20

Countries

  • Japan

Study Locations

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Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT02151721 on ClinicalTrials.gov