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

Inclusion Criteria:

1. Age ≥21 years

2. 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

3. Disease location amenable to biopsy in outpatient clinical setting or operative biopsy
within routine accepted schedule and practice of clinical care

4. ECOG performance status 0-1

5. 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

6. Willingness and ability to give signed written informed consent.

Exclusion Criteria:

1. Medical contraindication to biopsy of target lesion

2. Intercurrent illness likely to prevent protocol therapy or conventional planned
therapy

3. Prior daily use of tadalafil or other long-acting PDE5 inhibitors for one month or
greater

4. Known severe hypersensitivity to tadalafil or any of the excipients of this product

5. Current treatment with nitrates

6. Current systemic treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitor such
as ketoconazole or ritonavir

7. History of hypotension and/or blindness during prior treatment with tadalafil or other
PDE-5 inhibitors

8. Prior history of non-arterial ischemic optic retinopathy

9. Prior adverse reaction to diphtheria vaccine

10. Pregnant or breastfeeding; a negative pregnancy test is required within 14 days of
randomization for all women of childbearing potential.

11. 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

12. Treatment with a non-approved or investigational drug within 30 days before visit 1

13. Incomplete healing from previous oncologic or other major surgery

14. As judged by the investigator, any evidence of severe or uncontrolled systemic disease
(e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease)

15. Evidence of any other significant clinical disorder or laboratory finding that makes
it undesirable for the subject to participate in the trial

16. History of significant hypotensive episode requiring hospitalization

17. History of acute myocardial infarction within prior 3 months, uncontrolled angina,
uncontrolled arrhythmia, or uncontrolled congestive heart failure

18. 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

19. 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

20. Prior chronic immune suppressive state (AIDS, immunosuppressive therapy)