Clinical trial NCT01027676: Study of Vorinostat and Gefitinib in Relapsed/ or Refractory Patients With Advanced Non-small Cell Carcinoma (NSCLC)
Official title: Phase I/II Study of Vorinostat and Gefitinib in Relapsed/ or Refractory Patients With Advanced Non-small Cell Carcinoma (NSCLC)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Non-Small-Cell Lung Carcinoma
Keywords: Gefitinib
Vorinostat
Lead sponsor: National Cancer Center, Korea
Sponsor class: OTHER_GOV
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2009-12-09
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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 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.

Primary outcomes:
measure: Progression-Free Survival
timeFrame: every 8 weeks
Secondary outcomes:
measure: Overall Survival
timeFrame: every 8 weeks
measure: Objective Response rate
timeFrame: every 8 weeks
Other outcomes:
Locations:
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggi-do
Study officials:
affiliation: National Cancer Center
name: JI-YOUN HAN, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Han JY, Lee SH, Lee GK, Yun T, Lee YJ, Hwang KH, Kim JY, Kim HT. Phase I/II study of gefitinib (Iressa((R))) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2015 Mar;75(3):475-83. doi: 10.1007/s00280-014-2664-9. Epub 2015 Jan 1.