• Rate of Dose Limiting Toxicity (DLT) [ Time Frame: 2 years ]
  Rate of dose limiting toxicity at least possibly attributable to study treatment
• Overall Survival (OS) [ Time Frame: 12 months ]
  Overall survival at 12 months post-enrollment

• Response measured by RECIST 1.1 [ Time Frame: 12 months ]
• Progression free survival [ Time Frame: 2 years ]
• Adverse event rates [ Time Frame: 2 years ]

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.

• Head and Neck Cancer
• Head and Neck Squamous Cell Carcinoma
• Head and Neck Carcinoma
• Head and Neck Cancer Stage III
• Head and Neck Cancer Stage IV
• Head and Neck Cancer Metastatic
• Cancer
• Cancer of Esophagus
• Cancer, Metastatic
• Cancer of Head and Neck
• Cancer of Mouth
• Cancer of Neck

• Drug: Pembrolizumab
  200 mg intravenously every 3 weeks
  Other Name: Keytruda
• Drug: Tadalafil
  10 mg by mouth daily
  Other Name: Cialis

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).