Aerodigestive Tract Cancer, Esophageal Cancer, Head and Neck Cancer, Lung Cancer
Conditions
Keywords
resectable, stage I-III, NSCLC, vorinostat, esophagus, head and neck, proof of principle
Brief summary
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.
Interventions
DRUGVorinostat
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.
Sponsors
Merck Sharp & Dohme LLC
Dartmouth-Hitchcock Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Tumor Markers on Tumors of the Lung, Esophagus, or Head and Neck, After 7 Days of Treatment With Vorinostat | Baseline to Day 7 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Concentration of Vorinostat in Tumor Tissue | Day 7 from Baseline | Concentration of vorinostat in tumor tissue will be measured after 7 days of use of Vorinostat. |
| Effects of Vorinostat Treatment on Induction of Apoptosis or Necrosis in Treated vs. Untreated Tumors | Baseline to day 7 | 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. |
Countries
United States
Participant flow
Recruitment details
Patients with clinical Stage I, II, III A NSCLC or Stage I, II , III esophageal cancer or Stage I, II, III, IV A Head and Neck cancer and a pre-treatment biopsy having at least 3 unstained slides were eligible. Patients were recruited from the oncology clinic.
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat Vorinostat group | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Vorinostat |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 67 years STANDARD_DEVIATION 17.33 |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
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
Time frame: Baseline to Day 7
Population: Participants who had at least two days days of treatment with vorinostat.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Vorinostat | Changes in Tumor Markers on Tumors of the Lung, Esophagus, or Head and Neck, After 7 Days of Treatment With Vorinostat | Changes in Ki-67 expression by immunohistochemical | 67 percentage of change |
| Vorinostat | Changes in Tumor Markers on Tumors of the Lung, Esophagus, or Head and Neck, After 7 Days of Treatment With Vorinostat | Changes in cyclin D1 expression by immunohistochem | 40 percentage of change |
| Vorinostat | Changes in Tumor Markers on Tumors of the Lung, Esophagus, or Head and Neck, After 7 Days of Treatment With Vorinostat | Changes in cyclin E expression by immunohistochemi | 40 percentage of change |
Secondary
Concentration of Vorinostat in Tumor Tissue
Concentration of vorinostat in tumor tissue will be measured after 7 days of use of Vorinostat.
Time frame: Day 7 from Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat | Concentration of Vorinostat in Tumor Tissue | 42.6 ng/mg |
Secondary
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.
Time frame: Baseline to day 7
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Effects of Vorinostat Treatment on Induction of Apoptosis or Necrosis in Treated vs. Untreated Tumors | 1 score on a scale |