Study of Vorinostat and Gefitinib in Relapsed/ or Refractory Patients With Advanced Non-small Cell Carcinoma (NSCLC)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ji-youn Han, National Cancer Center, Korea
ClinicalTrials.gov Identifier:
NCT01027676
First received: December 8, 2009
Last updated: November 13, 2013
Last verified: November 2013
  Purpose

Gefitinib is an orally active epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) and produces 8-20% of response rates in patients with advanced non-small cell lung cancer (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. There is a strong synergistic antiproliferative effect of vorinostat in combination with gefitinib in NSCLC cells. Vorinostat increases expression of E-cadherin and ErbB-3, which results in increased sensitivity to gefitinib. Moreover, In-vitro studies have shown that vorinostat leads to acetylation and disruption of Hsp90, which may lead to decreases in activity of pro-growth and prosurvival client proteins (J Bio Chem 2005;280:26729, Br J Cancer 2006;95:S2). These findings suggest that combination of vorinostat with gefitinib may improve the efficacy of gefitinib in NSCLC.


Condition Intervention Phase
Non-Small-Cell Lung Carcinoma
Drug: Study treatment
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of Vorinostat and Gefitinib in Relapsed/ or Refractory Patients With Advanced Non-small Cell Carcinoma (NSCLC)

Resource links provided by NLM:


Further study details as provided by National Cancer Center, Korea:

Primary Outcome Measures:
  • Progression-Free Survival [ Time Frame: every 8 weeks ] [ Designated as safety issue: No ]
    The first day of treatment to the date that disease progression is reported or death date


Secondary Outcome Measures:
  • Overall Survival [ Time Frame: every 8 weeks ] [ Designated as safety issue: No ]
    The first day of treatment to the date that death is reported or last survival status reported or

  • Objective Response rate [ Time Frame: every 8 weeks ] [ Designated as safety issue: No ]
    The date of first evaluation to the date of disease progression


Estimated Enrollment: 50
Study Start Date: June 2010
Estimated Study Completion Date: March 2014
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: study arm
single arm Gefitinib plus vorinostat
Drug: Study treatment
Gefitinib 250mg/QD plus vorinostat D1~7 & D15-21 / QD q 4weeks

Detailed Description:

Phase I design

  • Three patients will be treated per cohort for one cycle (28 days per cycle).
  • If no DLTs are recorded, treatment will continue and three patients will be treated in the subsequent cohort.
  • However, if a patient develops a DLT, another three patients will be treated in this cohort for one cycle.
  • If there are no more DLTs, dose escalation continues.
  • If more than one of three patients develop a DLT in any cohort, another three patients will be treated in the next lower dosage cohort.
  • If no DLTs are recorded in any of the cohorts, cohort 3 will be expanded to six patients.
  • Up to 12 patients will be enrolled at the MTD.
  • The phase II dose for this combined treatment will be therefore defined as the highest dosage cohort in which six patients had been treated and there are less than three DLTs.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologic or cytologic diagnosis of NSCLC, Stage IV or selected stage IIIB (with positive pleural effusion or multiple ipsilateral lung nodules) according to the American Joint Committee on Cancer (AJCC).
  • Previously treated with at least one platinum-based chemotherapy.
  • Before study entry, a minimum of 28 days must have elapsed since any prior chemotherapy.
  • Prior radiation therapy is allowed as long as the irradiated area is not the only source of measurable disease.
  • No other forms of cancer therapy, such as radiation, immunotherapy for at least 2 weeks before the enrollment in study.
  • Performance status of 0-2 on the ECOG criteria.
  • At least one unidimensionally measurable lesion meeting Response Evaluation Criteria in Solid Tumors (Revised RECIST guideline version 1.1)
  • Estimated life expectancy of at least 8 weeks.
  • Patient compliance that allow adequate follow-up.
  • Adequate hematologic (WBC count 4,000/mm3, platelet count 150,000/mm3), hepatic (bilirubin level 1.5 mg/dL, AST/ALT 80 IU/L), and renal (creatinine concentration 1.5 mg/dL) function.
  • Informed consent from patient or patient's relative.
  • Males or females at least 18 years of age.
  • If female: childbearing potential either terminated by surgery, radiation, or menopause, or attenuated by use of an approved contraceptive method (intrauterine device [IUD], birth control pills, or barrier device) during and for 3 months after trial. If male, use of an approved contraceptive method during the study and 3 months afterwards. Females with childbearing potential must have a urine negative hCG test within 7 days prior to the study enrollment.
  • Patients with brain metastasis are allowed unless there were clinically significant neurological symptoms or signs

Exclusion Criteria:

  • Presence of small-cell lung cancer alone or with NSCLC
  • Unresolved chronic toxic effects from previous anticancer therapy: but patient could be enrolled, if they have recovered from any treatment-related toxicities NCI CTCAE grade ≤2
  • Inability to swallow tablets
  • Second primary malignancy (except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin or prior malignancy treated more than 5 years ago without recurrence).
  • More than three previous chemotherapy regimens for NSCLC
  • Previous treatment with any EGFR-TKI
  • Patients who have been exposed to any prior HDAC inhibitor, with the exception of exception of valpronic acid used for treating seizures, provided there is a 30-day washout period
  • Patients with active HIV or hepatitis B or C infection
  • Concomitant use of phenytoin, carbamazepine, rifampicin, barbiturates, cyclosporine A, valpronic acid, Phenobarbital, ketoconazole, coumarin-derivative anticoagulants or St John's wort; severe or uncontrolled systemic disease; clinically active interstitial lung disease (except uncomplicated lymphangitic carcinomatosis) pregnancy; and breastfeeding.
  • MI within preceding 6 months or symptomatic heart disease, including unstable angina, congestive heart failure or uncontrolled arrhythmia
  • Serious concomitant infection including postobstructive pneumonia
  • Major surgery other than biopsy within the past two weeks.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01027676

Locations
Korea, Republic of
National Cancer Center
Goyang-si, Gyeonggi-do, Korea, Republic of, 410-769
Sponsors and Collaborators
National Cancer Center, Korea
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: JI-YOUN HAN, M.D. National Cancer Center
  More Information

No publications provided

Responsible Party: Ji-youn Han, Head, Center for Lung Cancer, National Cancer Center, Korea
ClinicalTrials.gov Identifier: NCT01027676     History of Changes
Other Study ID Numbers: NCCCTS-09-433
Study First Received: December 8, 2009
Last Updated: November 13, 2013
Health Authority: Korea: Food and Drug Administration

Keywords provided by National Cancer Center, Korea:
Gefitinib
Vorinostat

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Vorinostat
Gefitinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on August 27, 2014