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Selected

Inclusion Criteria:

• - Patients (at least 18 years of age) must have recurrent or metastatic squamous cell carcinoma of the head and neck.

• - Presence of measurable disease.

• - Life expectancy of greater than 12 weeks.

• - Patients must have normal organ and marrow function.

Exclusion Criteria:

• - Prior therapy with an PD-1 or PD-L1 inhibitor in the recurrent or metastatic setting.

• - Uncontrolled central nervous system metastases (stable metastases permitted) - Active autoimmune disease.

• - Chemotherapy ≤28 days prior to first administration of study treatment and/or monoclonal antibody ≤8 weeks prior to first administration of study treatment.

• - Prior daily use of tadalafil or other long-acting PDE5 inhibitors for one month or greater within 3 months of trial enrollment.

• - Current use of all other long-acting PDE5 inhibitors.

• - 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.

• - Current treatment with guanylate cyclase (GC) stimulators such as riociguat.

• - History of hypotension and/or blindness and/or sensorineural hearing loss during prior treatment with tadalafil or other PDE-5 inhibitors.

• - History of known hereditary degenerative retinal disorders, including retinitis pigmentosa.

• - Prior history of non-arteritic anterior ischemic optic neuropathy.

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

• - History of stroke within prior 6 months.

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

• - Left ventricular outflow obstructions, such as aortic stenosis and idiopathic hypertrophic subaortic stenosis.

• - Angina requiring treatment with long-acting nitrates.

• - Angina requiring treatment with short-acting nitrates within 90 days of planned tadalafil administration.

• - Unstable angina within 90 days of visit 1 (Braunwald 1989) - 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: - Myocardial Infarction.

• - Coronary artery bypass graft surgery.

• - Percutaneous coronary intervention (for example, angioplasty or stent placement) - Any evidence of heart disease (NYHA ≥ Class II as defined in Protocol Attachment LVHG.

• - Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or chronic administration of >10 mg/day of prednisone or equivalent) - Prior organ transplantation.

• - Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).

Immune competent animal models of HNSCC demonstrate that combination PDE-5 inhibitor (tadalafil) and PD-1 inhibitor therapy is more effective than either therapy alone based on the concept of targeting multiple immune repressive abnormalities simultaneously (PD-1 checkpoint and myeloid suppressive pathways). This trial will test the hypothesis that combination PD-1 inhibition and PDE-5 inhibition can be safely co-administered, and secondarily test the hypothesis that the combination of both therapies will be more effective than PD-1 inhibition alone in recurrent/metastatic HNSCC.

Arms

Interventions