A Phase II Trial of Tadalafil in Patients With Squamous Cell Carcinoma of the Upper Aero Digestive Tract

Inclusion criteria

• Age ≥21 years
• Histologically confirmed, previously untreated invasive head and neck squamous cell carcinoma OR histologically confirmed not yet treated recurrent head and neck squamous cell carcinoma (must be at least 3 months after diagnosis and completion of treatment for primary disease or last recurrence). Patients may have local Stage I or II, or locoregionally advanced HNSCC Stage III or IV of the oral cavity, oropharynx, larynx, hypopharynx, or unknown primary, but no metastatic disease; Intent to treat with primary radiotherapy +/-chemotherapy
• Disease location amenable to biopsy in outpatient clinical setting or operative biopsy within routine accepted schedule and practice of clinical care
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Required laboratory data (to be obtained within 2 weeks of initiation):

• Platelets > 75,000/mm³
• Calculated Creatinine Clearance (CRCL)> 60 mL/min
• Total serum bilirubin < 1.5 mg/dL
• Willingness and ability to give signed written informed consent.

Exclusion criteria

• Medical contraindication to biopsy of target lesion
• Intercurrent illness likely to prevent protocol therapy or conventional planned therapy
• Prior daily use of tadalafil or other long-acting PDE5 inhibitors for one month or greater
• Known severe hypersensitivity to tadalafil or any of the excipients of this product
• Current treatment with nitrates
• Current systemic treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitor such as ketoconazole or ritonavir
• History of hypotension and/or blindness during prior treatment with tadalafil or other PDE5 inhibitors
• Prior history of non-arterial ischemic optic retinopathy
• Prior adverse reaction to diphtheria vaccine
• Pregnant or breastfeeding; a negative pregnancy test is required within 14 days of randomization for all women of childbearing potential.
• Concurrent malignancy or a history of previous malignancy treated with curative therapy within the last 3 months (other than squamous/basal cell cancer of the skin or cervical cancer), for which the survival prognosis is < 5 years
• Treatment with a non-approved or investigational drug within 30 days before visit 1
• Incomplete healing from previous oncologic or other major surgery
• As judged by the investigator, any evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease)
• Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the subject to participate in the trial
• History of significant hypotensive episode requiring hospitalization
• History of acute myocardial infarction within prior 3 months, uncontrolled angina, uncontrolled arrhythmia, or uncontrolled congestive heart failure
• History of any of the following cardiac conditions:

I. Angina requiring treatment with long-acting nitrates II. Angina requiring treatment with short-acting nitrates within 90 days of planned tadalafil administration III. Unstable angina within 90 days of visit 1 (Braunwald 1989) IV. Positive cardiac stress test without documented evidence of subsequent, effective cardiac intervention

• History of any of the following coronary conditions within 90 days of planned tadalafil administration:

I. Myocardial Infarction II. Coronary artery bypass graft surgery III. Percutaneous coronary intervention (for example, angioplasty or stent placement) IV. Any evidence of heart disease (NYHA≥Class III as defined in Protocol Attachment LVHG.3) within 6 months of planned tadalafil administration

• Prior chronic immune suppressive state (AIDS, immunosuppressive therapy)