UMIN-CTR Clinical Trial

Public title

Phase I of Vorinostat-Iressa combined therapy on resistance by BIM polymorphysim in EGFR Mutant Lung Cancer

Acronym

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

Scientific Title

Phase I of Vorinostat-Iressa combined therapy on resistance by BIM polymorphysim in EGFR Mutant Lung Cancer

Scientific Title:Acronym

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

Region

Japan

Condition

Non-small-cell lung cancer

Classification by specialty

Pneumology	Hematology and clinical oncology	Adult

Classification by malignancy

Malignancy

Genomic information

NO

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

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

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

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

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

Name of lead principal investigator

1st name
Middle name
Last name	Seiji Yano

Organization

Medical Oncology Cancer Research Institute, Kanazawa University

Division name

Medical Oncology

Zip code

Address

13-1 Takara-machi, Kanazawa, Ishikawa 920-0934

TEL

076-265-2780

Email

syano@staff.kanazawa-u.ac.jp

Name of contact person

1st name
Middle name
Last name	Shinji Takeuchi

Organization

Cancer Research Center, Kanazawa UNIversity

Division name

Medical Oncology

Zip code

Address

13-1 Takara-machi, Kanazawa, Ishikawa 920-0934

TEL

076-265-2794

Homepage URL

Email

takeuchi@staff.kanazawa-u.ac.jp

Institute

Cancer Research Center, Kanazawa University

Institute

Department

Personal name

Organization

Japan Agency for Medical Research and Development

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Japan

Co-sponsor

Nagoya University Hospital
Tohoku University Hospital
Shizuoka Cancer Center
Institute of Biomedical Research and Innovation Hospital

Name of secondary funder(s)

Organization

Address

Tel

Email

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

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）

Date of disclosure of the study information

2014

Year

09

Month

17

Day

URL releasing protocol

https://clinicaltrials.gov/ct2/show/record/NCT02151721?term=NCT02151721&rank=1

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

Results

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Enrolling by invitation

Date of protocol fixation

2013

Year

06

Month

22

Day

Date of IRB

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

Other related information

Registered date

2014

Year

09

Month

17

Day

Last modified on

2016

Year

08

Month

22

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017266