Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer (VICTORY-J)
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|ClinicalTrials.gov Identifier: NCT02151721|
Recruitment Status : Unknown
Verified February 2018 by Seiji Yano, M.D., Ph.D., Kanazawa University.
Recruitment status was: Active, not recruiting
First Posted : May 30, 2014
Last Update Posted : February 5, 2018
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Non-Small-Cell Lung Carcinoma||Drug: Vorinostat, gefitinib||Phase 1|
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer|
|Actual Study Start Date :||June 1, 2014|
|Estimated Primary Completion Date :||February 20, 2018|
|Estimated Study Completion Date :||February 20, 2018|
Experimental: vorinostat, gefitinib, combination
single arm vorinostat plus gefitinib
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
- MTD (Maximum Tolerated Dose) [ Time Frame: Second cycle (Day 28) ]MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02151721
|Nagoya University Graduate School of Medicine|
|Nagoya, Aichi, Japan, 466-8560|
|Institute of Biomedical Research and Innovation Hospital|
|Kobe, Hyogo-ken, Japan, 650-0047|
|Kanazawa University Hospital|
|Kanazawa, Ishikawa, Japan, 920-0934|
|Tohoku University Hospital|
|Sendai, Miyagi, Japan, 980-8574|
|Shizuoka Cancer Center|
|Sunto-gun, Shizuoka, Japan, 411-8777|
|Principal Investigator:||Seiji Yano, MD, PhD||Kanazawa University Hospital|