This study will examine the combination of pembrolizumab and tadalafil for safety and efficacy in advanced head and neck cancer.

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.

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

Selected 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.3) within 6 months of planned tadalafil administration

• 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).