Last updated on February 2018

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

Brief description of study

  • 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.

Detailed Study Description

  • A cohort of three patients will be treated at each dose level for one cycle (28 days per cycle).
    • Treatment will be continued if no DLTs are recorded, and three patients will be treated at the next higher dose level.
    • If a patient of the cohort develops a DLT, however, another cohort of three patients will be treated for 1 cycle.
    • If more DLTs do not develop, dose escalation continues.
    • If more than one of three patients develop a DLT at any dose level, another cohort of three patients will be treated at the next lower dose level.
    • If no DLTs are recorded in any of the cohorts, the number of patients per cohort will be increased from 3 to 6.
    • Up to 12 patients will be enrolled at the MTD.
    • Therefore, the phase II dose for this combined therapy will be defined as the highest dose level at which six patients were treated and less than three DLTs developed.

Clinical Study Identifier: NCT02151721

Contact Investigators or Research Sites near you

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Yoshinori Hasegawa, MD, PhD

Nagoya University Graduate School of Medicine
Nagoya, Japan

Nobuyuki Katakami, M.D. Ph.D.

Institute of Biomedical Research and Innovation Hospital
Kobe, Japan

Shinji Takeuchi, M.D.

Kanazawa University Hospital
Kanazawa, Japan

Akira Inoue, MD, PhD

Tohoku University Hospital
Sendai, Japan

Toshiaki Takahashi, MD, PhD

Shizuoka Cancer Center
Sunto-gun, Japan