A Clinical Trial to Validate Molecular Targets of Vorinostat in Patients With Aerodigestive Tract Cancer

The primary aim is to study the effects of vorinostat on cyclin E, cyclin D1 and Ki-67 expression in aerodigestive tract tumors (lung, esophagus, and head and neck). Secondary aims are: To evaluate the concentration of vorinostat in tumor tissue and to correlate tumor tissue distribution with the plasma level in these patients; to perform exploratory analyses of the effects of vorinostat on the induction of apoptosis or necrosis in treated as compared to untreated tumors and on expression of p21, p27, EGFR and phospho-EGFR in aerodigestive tract tumors.

Study Overview

• Status: Completed
• Conditions: Head and Neck Cancer; Esophageal Cancer; Lung Cancer; Aerodigestive Tract Cancer
• Intervention / Treatment: Drug: Vorinostat

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All patients must have pathological confirmation of non small cell carcinoma of the aerodigestive tract (lung, esophagus, head and neck cancer).
• Patients must have resectable clinical stage I - III non small cell lung, clinical stage I-III esophageal cancer, or stage I-IV A head and neck cancer.
• Age >18 years.
• Adequate hepatic and renal function documented prior to study entry to include: hepatic transaminases (AST or ALT) ≤ 2.0 times the upper limits of normal, total bilirubin ≤ 1.5 times the upper limits of normal, serum creatinine ≤ 1.5 times the upper limit of normal or estimated creatinine clearance ≥ 60 mL/min.
• All patients must be medical candidates for surgical resection of their non-small cell lung cancer.
• All patients must give informed consent indicating they are aware of the investigational nature of this treatment.

Exclusion Criteria:

• Patients may not have received radiation therapy for their aerodigestive tract cancer.
• Patients may not have received chemotherapy for their aerodigestive tract cancer.
• Women must be surgically sterilized or post-menopausal or women of childbearing potential must be using an adequate method of contraception. Women of childbearing potential must be using at least one of the following: oral, implanted, injectable contraceptive hormones, or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or have a partner that is sterile (e.g., vasectomy). Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to start of study therapy.
• Women who are pregnant or breast-feeding will be excluded.
• Male patients with partners of childbearing potential not using an adequate method of birth control as described in the previous paragraph will be excluded.
• Patients with gastrointestinal abnormalities including: inability to take oral medication, requirement for intravenous alimentation, or prior surgical procedures affecting absorption will be excluded.
• A serious uncontrolled medical disorder or active infection which would impair their ability to receive study treatment will be excluded. Significant cardiac disease, including uncontrolled high blood pressure, unstable angina, congestive heart failure, myocardial infarction within the previous 3 months or serious cardiac arrythmias will be excluded. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol will be excluded.
• Patients with active HIV, Hepatitis C virus (HCV) or Hepatitis B virus (HBV) infection.
• No prior treatment with histone deacetylase (HDAC) inhibitors. Valproic acid is acceptable if not used as anticancer therapy and a 30-day wash-out period is allowed.
• Exposure to other investigational agents within 30 days of study inclusion
• Patients with a "currently active" second malignancy, other than nonmelanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled. Patients would not be considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for >5 years or are considered by their physician to be at less than 30% risk of relapse.
• Patients with history of pulmonary embolism who are not receiving anticoagulation, will be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Vorinostat 400 mg; Vorinostat will be administered orally once daily in an open-labeled unblinded manner to all subjects enrolled in the study. Subjects will received 400 mg once daily on a continuous daily basis for 7 to 10 days prior to surgical resection.

Drug: Vorinostat; Vorinostat will be administered orally once daily in an open-labeled, unblinded manner to all subjects enrolled in the study. Subjects will receive vorinostat 400 mg once daily on a continuous daily basis for 7 to 10 days prior to surgical resection. Vorinostat should be taken with food within 0 to 30 minutes of a meal if possible. Patients should take the medication at approximately the same time each day on an ongoing basis. Missed doses will not be made up.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Tumor Markers on Tumors of the Lung, Esophagus, or Head and Neck, After 7 Days of Treatment With Vorinostat	Immunohistochemical score, defined as: 0, no tumor cells staining positive; 1+, 0% to 50% of tumor cells staining positive; 2+, 50% to 75% of tumor cells staining positive; and 3+, 75% to 100% of tumor cells staining positive. The change in the score before and after treatment is percentage - 0-100	Baseline to Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of Vorinostat in Tumor Tissue	Concentration of vorinostat in tumor tissue will be measured after 7 days of use of Vorinostat.	Day 7 from Baseline
Effects of Vorinostat Treatment on Induction of Apoptosis or Necrosis in Treated vs. Untreated Tumors	vorinostat's effects on induction of apoptosis or necrosis in treated vs untreated tumors and on p21, p27, EGFR, and phospho-EGFR expression aerodigestive tract tumors. Immunohistochemical score is defined as follows: 0, no tumor cells staining positive; 1+, 0% to 50% of tumor cells staining positive; 2+, 50% to 75% of tumor cells staining positive; and 3+, 75% to 100% of tumor cells staining positive.	Baseline to day 7

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Konstantin H. Dragnev, MD, Dartmouth-Hitchcock Medical Center

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: August 13, 2008
• First Submitted That Met QC Criteria: August 14, 2008
• First Posted (Estimate): August 15, 2008

Study Record Updates

• Last Update Posted (Actual): October 12, 2018
• Last Update Submitted That Met QC Criteria: October 8, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: NSCLC; resectable; head and neck; stage I-III; vorinostat; esophagus; proof of principle
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Vorinostat
• Other Study ID Numbers: D-0828