Non-Small-Cell Lung CarcinomaPhase 1VICTORY-JNCT02151721
Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer
A Phase 1 study testing Vorinostat, gefitinib in people with Non-Small-Cell Lung Carcinoma, run by Kanazawa University at 5 sites in Japan.
Trial 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. Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Non-Small-Cell Lung Carcinoma
- What is being tested?
- Vorinostat, gefitinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 5 sitesJapan
- Study dates
- 1 Jun 2014to 20 Feb 2018
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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.
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- 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)
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Japan5 sites
Kanazawa University Hospital
Kanazawa, Ishikawa-ken, 920-0934
Institute of Biomedical Research and Innovation Hospital
Kobe, Hyōgo, 650-0047
Nagoya University Graduate School of Medicine
Nagoya, Aichi-ken, 466-8560
Tohoku University Hospital
Sendai, Miyagi, 980-8574
Shizuoka Cancer Center
Sunto-gun, Shizuoka, 411-8777
About this 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.
Read the 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
- Being tested
- Vorinostat, gefitinib
- Keywords
- Vorinostat, Gefitinib, BIM polymorphism, EGFR-TKI resistance
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Vorinostat, gefitinibDrug
Also called Zolinza, Iressa
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
| Study group | Role | What they receive |
|---|---|---|
| vorinostat, gefitinib, combination | Experimental | single arm vorinostat plus gefitinib Receives: Drug: Vorinostat, gefitinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
MTD (Maximum Tolerated Dose)
MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.
Measured: Second cycle (Day 28)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 May 2014 (estimated)
- Study start1 Jun 2014
- Primary completion20 Feb 2018 (estimated)
- Study completion20 Feb 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-Small-Cell Lung CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Kanazawa University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Seiji Yano, M.D., Ph.D., Kanazawa University
- Investigators
- Seiji Yano, MD, PhD, Principal investigator, Kanazawa University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02151721
- Sponsor's protocol ID
- H25-S-I-005
- Acronym
- VICTORY-J
- Status last verified
- Feb 2018
- First submitted
- 28 May 2014
- Last updated
- 5 Feb 2018
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The 12th patient in stage 3 was registered.
Study at a glance
From the registry record, last updated by the sponsor on 5 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer
- ClinicalTrials.gov ID
- NCT02151721
- Acronym / sponsor ID
- VICTORY-J / H25-S-I-005
- Conditions
- Non-Small-Cell Lung Carcinoma
- Keywords
- Vorinostat, Gefitinib, BIM polymorphism, EGFR-TKI resistance
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Kanazawa UniversityUniversity, hospital or other
- Study start
- 1 Jun 2014 (actual)
- Primary completion
- 20 Feb 2018 (estimated)
- Study completion
- 20 Feb 2018 (estimated)
- First posted
- 30 May 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| vorinostat, gefitinib, combination | Experimental | Drug: Vorinostat, gefitinibsingle arm vorinostat plus gefitinib |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- 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)
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Vorinostat, gefitinibAlso: Zolinza, IressaVorinostat 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 | Drug | vorinostat, gefitinib, combination |
Primary outcome
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.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Feb 2018.
- Individual participant dataSharing planned: Yes. The 12th patient in stage 3 was registered.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Seiji Yano, MD, PhD principal investigator
Kanazawa University Hospital
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Vorinostat, gefitinib in people with Non-Small-Cell Lung Carcinoma, run by Kanazawa University at 5 sites in Japan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 5 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Japan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
MTD (Maximum Tolerated Dose) (time frame: Second cycle (Day 28)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Feb 2018.