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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. 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
Information provided by (Responsible Party):
Seiji Yano, M.D., Ph.D., Kanazawa University

Brief 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.

Condition or disease Intervention/treatment Phase
Non-Small-Cell Lung Carcinoma Drug: Vorinostat, gefitinib Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
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
Other Names:
  • Zolinza
  • Iressa

Primary Outcome Measures :
  1. 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically or cytologically diagnosed NSCLC (excluding squamous cell carcinoma)
  • NSCLC of clinicopathologic stage IIIB or IV for which radical radiation therapy is impracticable, or recurrence after surgery
  • EGFR mutations (deletion of exon 19 and L858R mutation of exon 21) for which the clinical benefits of an EGFR-TKI (gefitinib or erlotinib) are recognized by testing methods that are listed by the national health insurance
  • Having a history of treatment with an EGFR-TKI (gefitinib or erlotinib) and a history of pathology deterioration during treatment
  • Having a history of treatment with cytotoxic anticancer agents (not including pre- or postoperative chemotherapy that has passed 1 or more year from the day of final administration)
  • Confirmed BIM polymorphism by the PCR fragment analytical method and the sequence method at the central laboratory
  • Having a lesion measureable according to the RECIST guidelines revised version 1.1 (20 mm or larger in 10-mm slice CT, 10 mm or larger in 5-mm slice CT, 15 mm or larger in the minor axis of a lymph node). Confirmed advance of the pathology at the site of irradiation after irradiation in a patient who only has an irradiated lesion
  • Ages 20 years and older
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 at the time of consent acquisition
  • Having adequate bone marrow (neutrophil count: 1,500/L, Platelet count: 100,000/L), hepatic (total bilirubin level: 1.5-fold or less of the upper limit of reference value at each institution), renal (creatinine level: 1.5 mg/dL), and respiratory functions (PaO2: 70 torr or SpO2: 94%) within 14 days before entry.
  • An estimated life expectancy of 12 or more weeks after the onset of protocol treatment
  • A patient whose acute toxicities of prior treatments have recovered to the baseline level in the most recent prior treatment, excepting adverse events considered not to be of safety concern at the discretion of the investigator (subinvestigator)
  • A patient negative for the urinary pregnancy test to be performed at the time of screening prior to the onset of protocol treatment
  • Acquisition of written informed consent to participate in the present study from the patient after receiving a satisfactory explanation about study details

Exclusion Criteria:

  • Within 4 weeks after the final administration of a cytotoxic anticancer agent. Allowable enrollment when a 7-day washout is completed after the final administration of an EGFR-TKI. Surgery of a primary tumor or to the mediastinum must be completed at least 6 months before the onset of protocol treatment.
  • Radiotherapy to the lungs considered necessary at the time of study entry or in the near future.
  • Having an interstitial lung disease (including acute pulmonary disorder, interstitial pneumonia, and drug inducibility) or having a history thereof.
  • Having radiation pneumonitis or having a history thereof.
  • Having a large volume of or uncontrollable pleural effusion, ascites, or pericardial effusion
  • Detection of known EGFR-TKI resistance acquired by mutations of the genes, e.g., T790M.
  • Having a serious infection and other serious complications (e.g., gastrointestinal bleeding).
  • Suffering from a severe or poorly controlled systemic disease (e.g., unstable or decompensated respiratory disease, heart disease, renal disease, and liver disease)
  • Having an active, as well as poorly controlled or symptomatic metastasis to the central nervous system (involving cerebral edema, spinal cord compression, carcinomatous meningitis, leptomeningeal disease, or invasion due to disease progress). Even with a history of metastasis to the central nervous system or of spinal compression.
  • Having an active double cancer.
  • Verified HBs antigen positivity or HCV antibody positivity (excluding the case of confirmed HCV-RNA negativity)

Information from the National Library of Medicine

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 identifier (NCT number): NCT02151721

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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
Sponsors and Collaborators
Kanazawa University
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Principal Investigator: Seiji Yano, MD, PhD Kanazawa University Hospital
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Responsible Party: Seiji Yano, M.D., Ph.D., Chairman, Division of Medical Oncology Cancer Research Institute, Kanazawa University., Kanazawa University Identifier: NCT02151721    
Other Study ID Numbers: H25-S-I-005
First Posted: May 30, 2014    Key Record Dates
Last Update Posted: February 5, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The 12th patient in stage 3 was registered.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Seiji Yano, M.D., Ph.D., Kanazawa University:
BIM polymorphism
EGFR-TKI resistance
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Histone Deacetylase Inhibitors