UMIN-CTR Clinical Trial

Basic information
Official scientific title of the study	Phase I of Vorinostat-Iressa combined therapy on resistance by BIM polymorphysim in EGFR Mutant Lung Cancer
Title of the study (Brief title)	VICTORY-J(Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer-JAPAN)
Region	Japan

Condition
Condition	Non-small-cell lung cancer
Classification by specialty	Pneumology Hematology and clinical oncology Adult
Classification by malignancy	Malignancy
Genomic information	NO

Objectives
Narrative objectives1	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.
Basic objectives2	Safety,Efficacy
Basic objectives -Others
Trial characteristics_1	Exploratory
Trial characteristics_2	Others
Developmental phase	Phase I

Assessment
Primary outcomes	MTD (Maximum Tolerated Dose) defined as the highest dose level at which 2 of 6 patients experienced a DLT.
Key secondary outcomes	1)Safety (adverse events generated in from therapy start to the end of dosage end 30th of vorinostat 2)Blood concetnration after administration of vorinostat and gefitinib 3)progression free survival (PFS) period 4)Overall survival (OS) rate 5)Response rate (PR) 6)A response period and complete response period 7)Disease control rate (DCR) 8)Pharmacodynamic effect

Base
Study type	Interventional

Study design
Basic design	Single arm
Randomization	Non-randomized
Randomization unit
Blinding	Open -no one is blinded
Control	Uncontrolled
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms	1
Purpose of intervention	Treatment
Type of intervention	Medicine
Interventions/Control_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.
Interventions/Control_2
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	20 years-old <=
Age-upper limit	Not applicable
Gender	Male and Female
Key inclusion criteria	1)Histologically or cytologically diagnosed NSCLC (excluding squamous cell carcinoma) 3)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 4)Having a history of treatment with an EGFR-TKI (gefitinib or erlotinib) and a history of pathology deterioration during treatment 6)Confirmed BIM polymorphism by the PCR fragment analytical method and the sequence method at the central laboratory 7)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 8)Ages 20 years and older 9)Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 at the time of consent acquisition
Key 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. Suffering from a severe or poorly controlled systemic disease (e.g., unstable or decompensated respiratory disease, heart disease, renal disease, and liver disease)
Target sample size	18

Research contact person
Name of lead principal investigator	Seiji Yano
Organization	Medical Oncology Cancer Research Institute, Kanazawa University
Division name	Medical Oncology
Address	13-1 Takara-machi, Kanazawa, Ishikawa 920-0934
TEL	076-265-2780
Email	syano@staff.kanazawa-u.ac.jp

Public contact
Name of contact person	Shinji Takeuchi
Organization	Cancer Research Center, Kanazawa UNIversity
Division name	Medical Oncology
Address	13-1 Takara-machi, Kanazawa, Ishikawa 920-0934
TEL	076-265-2794
Homepage URL
Email	takeuchi@staff.kanazawa-u.ac.jp

Sponsor
Institute	Cancer Research Center, Kanazawa University
Institute
Department

Funding Source
Organization	Japan Agency for Medical Research and Development
Organization
Division
Category of Funding Organization	Japanese Governmental office
Nationality of Funding Organization	Japan

Other related organizations
Co-sponsor	Nagoya University Hospital Tohoku University Hospital Shizuoka Cancer Center Institute of Biomedical Research and Innovation Hospital
Name of secondary funｄer(s)

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions	金沢大学病院（石川県）、東北大学病院（宮城県）、名古屋大学医学部附属病院（愛知県）、静岡県立静岡がんセンター、先端医療センター（兵庫県）

Other administrative information
Date of disclosure of the study information	2014 Year 09 Month 17 Day

Progress
Recruitment status	Enrolling by invitation
Date of protocol fixation	2013 Year 06 Month 22 Day
Anticipated trial start date	2014 Year 05 Month 30 Day
Last follow-up date	2016 Year 04 Month 30 Day
Date of closure to data entry	2016 Year 05 Month 30 Day
Date trial data considered complete	2016 Year 06 Month 30 Day
Date analysis concluded	2016 Year 09 Month 30 Day

Related information
URL releasing protocol	https://clinicaltrials.gov/ct2/show/record/NCT02151721?term=NCT02151721&rank=1
Publication of results	Unpublished
URL releasing results
Results
Other related information

Management information
Registered date	2014 Year 09 Month 17 Day
Last modified on	2016 Year 08 Month 22 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017266