Intervention: Tadalafil
Trial phase: Phase 2
ATC code: C02KX52 | C02KX54 | G04BE08 | G04CA54 | G04CB51
SMILES: [H][C@]12Cc3c([nH]c4ccccc34)[C@@H](c3ccc4c(c3)OCO4)N1C(=O)CN(C)C2=O
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 40
Group description: Patients received 20 mg tadalafil capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment
Eligibility criteria:
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)