Head and neck squamous cell carcinoma (HNSCC) is a lethal solid malignancy with 5 year survival estimates of approximately 50%, and is associated with a high rate of systemic immune impairment as well as evasion of a tumor specific immune response. Preclinical and clinical data have shown that phosphodiesterase 5 (PDE5) inhibitors (tadalafil) can be used to augment immune function in HNSCC patients through inhibition of the cancer-induced myeloid derived suppressor cells (MDSCs).

A multi site phase II, randomized, prospective, biomarker endpoint trial to determine optimum timing and design of PDE5 antitumor immunotherapy (tadalafil) in conjunction with conventional therapy for HNSCC.

40 patients with biopsy proven HNSCC will be randomized to receive tadalafil (n=25) or placebo (n=15) for at least 10-14 days before starting conventional therapy and continuing until 90 days after completion of conventional therapy. Tumor-specific T cell responses will be assessed using HNSCC cell lines, in blood collected before initiation of tadalafil/placebo and at 60 and 90 days after completion of conventional therapy. Number and function of MDSC and Treg cells will be assessed before and at 60 and 90 days after completion of conventional therapy. Prevnar 13® vaccine will be administered 10-14 days after commencing tadalafil/placebo (before conventional therapy begins) and again at 60 days after completion of conventional therapy. Vaccine-specific responses assessed at 60 and 90 days post-conventional therapy will be used to measure the ability of tadalafil to augment immune response to vaccine.

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. Eastern Cooperative Oncology Group (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 PDE5 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)