Head and Neck Cancer
Conditions
Keywords
stage I squamous cell carcinoma of the lip and oral cavity, stage I squamous cell carcinoma of the oropharynx, stage II squamous cell carcinoma of the lip and oral cavity, stage II squamous cell carcinoma of the oropharynx, stage III squamous cell carcinoma of the oropharynx, stage III squamous cell carcinoma of the lip and oral cavity, stage IV squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the lip and oral cavity, stage I verrucous carcinoma of the oral cavity, stage II verrucous carcinoma of the oral cavity, stage III verrucous carcinoma of the oral cavity, stage IV verrucous carcinoma of the oral cavity
Brief summary
RATIONALE: Biological therapies, such as tadalafil, may stimulate the immune system in different ways and stop tumor cells from growing. PURPOSE: This randomized clinical trial is studying how well tadalafil works in treating patients who are undergoing surgery for cancer of the oral cavity or oropharynx.
Detailed description
OBJECTIVES: * To analyze the phenotype and the function of the tumor-induced suppressive network associated with squamous cell carcinoma (SCC) of the head and neck in patients with SCC of the oral cavity or oropharynx treated with tadalafil followed by definitive surgical resection. * To analyze the immune response before and after treatment with tadalafil to determine whether or not tadalafil treatment modulates in these patients. * To compare two doses of tadalafil to determine whether there are measurable differences in immune response in these patients. * To analyze treatment-related side effects of tadalafil at each of the two doses tested in these patients. OUTLINE: Patients are randomized to 1 of 3 treatment arms. * Arm I: Patients receive oral tadalafil once daily on days 1-20 in the absence of unacceptable toxicity. * Arm II: Patients receive oral tadalafil (at a higher dose than in arm I) once daily on days 1-20 in the absence of unacceptable toxicity. * Arm III: Patients receive oral placebo once daily on days 1-20 in the absence of unacceptable toxicity. All patients undergo scheduled definitive surgical resection on day 23. Patients undergo blood sample collection at baseline, on day 20, and at 6 weeks after surgical resection for correlative laboratory studies. Patients also undergo tumor tissue sample collection at baseline and at the time of surgical resection. Samples are analyzed for immunological markers by Fluorescence-activated cell sorting (FACS) and Immunohistochemistry (IHC). After completion of study treatment, patients are followed periodically for at least 3 years.
Interventions
DRUGTadalafil
Given orally
OTHERPlacebo
Given orally
Sponsors
Donald T. Weed
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Patients with surgically resectable oral cavity SCC, all subsites, T1 - T4, N0 - N3 * Patients with surgically resectable oropharyngeal SCC, all subsites, T1 - T2, N0 - N1 * Patients with surgically resectable T4 oropharyngeal SCC, all subsites, N0 - N3 * Patients must be 18 years old or older
Exclusion criteria
* Patients with previous surgical resection, radiation, or chemotherapy will be excluded to rule out possible effects of local tissue changes secondary to previous treatment * Patients with surgically unresectable disease at primary site or regional lymph nodes * Patients with T1 - T2 SCC oropharynx, N2 - N3 * Patients with T3 SCC oropharynx , N0 - N3 * Any patient for whom non-surgical therapy is recommended as treatment of choice after multidisciplinary treatment evaluation * Patients with an altered mental status or not capacitated for their medical decision making * Patients with severe or unstable cardiac or cerebrovascular disease are excluded * myocardial infarction within the last 90 days * unstable angina or angina occurring during sexual intercourse * New York Heart Association Class 2 or greater heart failure in the last 6 months * uncontrolled arrhythmias * hypotension (\<90/50 mm Hg), or uncontrolled hypertension (\>170/100 mm Hg) * stroke within the last 6 months * Left ventricle outflow obstruction. * Pregnant and nursing mothers will not be enrolled given unknown effects to offspring * Concurrent nitrate, alpha-blocker, or cytochrome P-450 inhibitor use * Renal Insufficiency defined as creatinine clearance less than 51. * Creatinine clearance will be determined by the following Cockcroft-Gault Equation: (140-age) \* (Wt in kg) \* (0.85 if female) / (72 \* Cr) * Patients with hepatic insufficiency. * Patients currently taking a Phosphodiesterase (PDE) inhibitors for erectile dysfunction * Patients who are immunocompromised, for reasons not directly related to patients malignancy * Patients with significant alcohol or drug abuse * Patients with unilateral blindness, hereditary retinal disorders, or increased risk of blindness * Patients with unilateral deafness, history of hearing loss, hearing aid dependence, or clinically evident hearing loss
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ratio of MDSC Concentration in the Blood | Baseline, End of Treatment at time of Surgery | Ratio of the number of Myeloid Derived Suppressor Cells (MDSC) in the Blood, per treatment group, from Baseline to End of Treatment at Time of Surgery. |
| Ratio of T-reg Cell Concentration in the Blood | Baseline, End of Treatment at Time of Surgery | Ratio of the number of regulatory T cells in the blood, per treatment group, from Baseline to End of Treatment at Time of Surgery.. |
| Ratio of Tumor-specific T-cell Concentration in the Blood | Baseline, End of Treatment at Time of Surgery | Ratio of the number of tumor specific T cells in the blood, per treatment group, from Baseline to End of Treatment at Time of Surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Optimal Dosing Schedule for Tadalafil | Baseline, End of Treatment at Time of Surgery. | — |
| Number of Participants Experiencing Adverse Events | From Day 1 to Day 20 | Assessment of Treatment-related Side Effects. Number of participants experiencing adverse events |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A - Tadalafil 10mg Patients will receive 10mg/day Tadalafil orally on days 1 - 20 in the absence of unacceptable toxicity.
Tadalafil: Given orally | 15 |
| Arm B - Tadalafil 20mg Patients will receive 20mg/day Tadalafil orally on days 1 - 20 in the absence of unacceptable toxicity.
Tadalafil: Given orally | 15 |
| Arm C - Placebo Patients receive oral placebo once daily on days 1-20 in the absence of unacceptable toxicity.
Placebo: Given orally | 5 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 0 |
Baseline characteristics
| Characteristic | Arm A - Tadalafil 10mg | Arm B - Tadalafil 20mg | Arm C - Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 61 years | 54 years | 67 years | 63 years |
| Age, Customized 50 to 59 years of age | 5 participants | 2 participants | 0 participants | 7 participants |
| Age, Customized < 50 years of age | 2 participants | 6 participants | 0 participants | 8 participants |
| Age, Customized 60 to 69 years of age | 5 participants | 3 participants | 4 participants | 12 participants |
| Age, Customized 70+ years of age | 3 participants | 4 participants | 1 participants | 8 participants |
| Alcohol Use Current Use | 11 participants | 8 participants | 4 participants | 23 participants |
| Alcohol Use Never | 2 participants | 2 participants | 1 participants | 5 participants |
| Alcohol Use Past Use | 2 participants | 5 participants | 0 participants | 7 participants |
| N Stage - Regional Lymph Nodes N0 | 7 participants | 9 participants | 4 participants | 20 participants |
| N Stage - Regional Lymph Nodes N1 | 2 participants | 1 participants | 1 participants | 4 participants |
| N Stage - Regional Lymph Nodes N2b | 4 participants | 3 participants | 0 participants | 7 participants |
| N Stage - Regional Lymph Nodes N2c | 1 participants | 2 participants | 0 participants | 3 participants |
| N Stage - Regional Lymph Nodes N3 | 1 participants | 0 participants | 0 participants | 1 participants |
| Positive for Human Papillomavirus (HPV+) No | 12 participants | 14 participants | 5 participants | 31 participants |
| Positive for Human Papillomavirus (HPV+) Yes | 3 participants | 1 participants | 0 participants | 4 participants |
| Pre-Operative Treatment No | 10 participants | 13 participants | 3 participants | 26 participants |
| Pre-Operative Treatment Yes | 5 participants | 2 participants | 2 participants | 9 participants |
| Pre-Operative Treatment, Details Chemo + Radiation | 1 participants | 1 participants | 2 participants | 4 participants |
| Pre-Operative Treatment, Details No | 10 participants | 13 participants | 3 participants | 26 participants |
| Pre-Operative Treatment, Details Radiation only | 4 participants | 1 participants | 0 participants | 5 participants |
| Race/Ethnicity, Customized Hispanic | 3 participants | 5 participants | 2 participants | 10 participants |
| Race/Ethnicity, Customized Not Reported | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized South Asian | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White, Non-Hispanic | 12 participants | 8 participants | 3 participants | 23 participants |
| Region of Enrollment United States | 15 participants | 15 participants | 5 participants | 35 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 12 Participants | 11 Participants | 4 Participants | 27 Participants |
| Site Oral Cavity | 13 participants | 14 participants | 4 participants | 31 participants |
| Site Oro Pharynx | 2 participants | 1 participants | 1 participants | 4 participants |
| Tobacco Use Current | 9 participants | 9 participants | 0 participants | 18 participants |
| Tobacco Use Never | 3 participants | 2 participants | 1 participants | 6 participants |
| Tobacco Use Quit < 20 years ago | 3 participants | 1 participants | 4 participants | 8 participants |
| Tobacco Use Quit > 20 years ago | 0 participants | 3 participants | 0 participants | 3 participants |
| T-Stage T1 | 1 participants | 7 participants | 1 participants | 9 participants |
| T-Stage T2 | 9 participants | 4 participants | 2 participants | 15 participants |
| T-Stage T3 | 1 participants | 0 participants | 1 participants | 2 participants |
| T-Stage T4 | 4 participants | 4 participants | 1 participants | 9 participants |
| Tumor size (cm) Mean | 3.7 cm STANDARD_DEVIATION 1.8 | 2.4 cm STANDARD_DEVIATION 1.3 | 3.5 cm STANDARD_DEVIATION 1.9 | 3.1 cm STANDARD_DEVIATION 1.7 |
| Tumor Size (cm) Median | 3 cm | 2.1 cm | 4 cm | 3 cm |
| Type of Tobacco Use Cigarettes | 12 participants | 11 participants | 4 participants | 27 participants |
| Type of Tobacco Use Cigar/Pipe | 0 participants | 1 participants | 0 participants | 1 participants |
| Type of Tobacco Use Never | 3 participants | 2 participants | 1 participants | 6 participants |
| Type of Tobacco Use Snuff/Chew/Smokeless | 0 participants | 1 participants | 0 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 15 | 8 / 15 | 3 / 5 |
| serious Total, serious adverse events | 1 / 15 | 2 / 15 | 0 / 5 |
Outcome results
Primary
Ratio of MDSC Concentration in the Blood
Ratio of the number of Myeloid Derived Suppressor Cells (MDSC) in the Blood, per treatment group, from Baseline to End of Treatment at Time of Surgery.
Time frame: Baseline, End of Treatment at time of Surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Tadalafil 10mg | Ratio of MDSC Concentration in the Blood | 0.7680 ratio from baseline |
| Arm B - Tadalafil 20mg | Ratio of MDSC Concentration in the Blood | 0.7919 ratio from baseline |
| Arm C - Placebo | Ratio of MDSC Concentration in the Blood | 0.9876 ratio from baseline |
Primary
Ratio of T-reg Cell Concentration in the Blood
Ratio of the number of regulatory T cells in the blood, per treatment group, from Baseline to End of Treatment at Time of Surgery..
Time frame: Baseline, End of Treatment at Time of Surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Tadalafil 10mg | Ratio of T-reg Cell Concentration in the Blood | 0.7776 ratio from baseline |
| Arm B - Tadalafil 20mg | Ratio of T-reg Cell Concentration in the Blood | 0.6789 ratio from baseline |
| Arm C - Placebo | Ratio of T-reg Cell Concentration in the Blood | 0.8421 ratio from baseline |
Primary
Ratio of Tumor-specific T-cell Concentration in the Blood
Ratio of the number of tumor specific T cells in the blood, per treatment group, from Baseline to End of Treatment at Time of Surgery.
Time frame: Baseline, End of Treatment at Time of Surgery
Population: Data for 31 patients were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Tadalafil 10mg | Ratio of Tumor-specific T-cell Concentration in the Blood | 1.7401 ratio from baseline |
| Arm B - Tadalafil 20mg | Ratio of Tumor-specific T-cell Concentration in the Blood | 1.9020 ratio from baseline |
| Arm C - Placebo | Ratio of Tumor-specific T-cell Concentration in the Blood | 1.0933 ratio from baseline |
Secondary
Number of Participants Experiencing Adverse Events
Assessment of Treatment-related Side Effects. Number of participants experiencing adverse events
Time frame: From Day 1 to Day 20
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Tadalafil 10mg | Number of Participants Experiencing Adverse Events | 4 participants |
| Arm B - Tadalafil 20mg | Number of Participants Experiencing Adverse Events | 10 participants |
| Arm C - Placebo | Number of Participants Experiencing Adverse Events | 3 participants |
Secondary
Optimal Dosing Schedule for Tadalafil
Time frame: Baseline, End of Treatment at Time of Surgery.
Population: Optimal dosing schedule of Tadalafil not determined due to no proven superiority of one dosing arm over the other.