NCT02151721

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

• Status: Unknown
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 12 (actual)
• Sponsor: Kanazawa University · Academic / Other
• Sex: All
• Age: 20 Years
• Healthy volunteers: Not accepted

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.

Detailed 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.

Conditions

• Non-Small-Cell Lung Carcinoma

Interventions

Type	Name	Description
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

Timeline

• Start date: 2014-06-01
• Primary completion: 2018-02-20
• Completion: 2018-02-20
• First posted: 2014-05-30
• Last updated: 2018-02-05

Locations

5 sites across 1 country: Japan