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

Sponsor
Kanazawa University
Study ID
NCT02151721
Phase
PHASE1
Status
Unknown

Conditions

  • Non-Small-Cell Lung Carcinoma

Eligibility Criteria

Sex
ALL
Age
20 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Vorinostat, gefitinib — DRUG
    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

Study Details

* 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.

Key Dates

Start date
Jun 1, 2014
Status verified
Feb 2018
Primary completion
Feb 20, 2018
Completion
Feb 20, 2018

Study Design

Enrollment
12 participants (actual)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: vorinostat, gefitinib, combination
    single arm vorinostat plus gefitinib

Primary Outcome Measure

MTD (Maximum Tolerated Dose) [ Time Frame: Second cycle (Day 28) ]

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