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

• Status: Unknown status
• Trial end date: 2014-03-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Cancer Center, Korea
• Collaborator: Merck Sharp & Dohme Corp.
• Treatments: Gefitinib; Vorinostat

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.