Tadalafil and Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Cancer

Inclusion Criteria

• Patients must have histologically or cytologically confirmed squamous cell carcinoma of the head and neck not amenable to curative intent therapy
• Presence of measurable disease via RECIST 1.1 criteria. Measurable disease in a previously radiated field is acceptable as long as there has been documented progression since completion of radiation
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Life expectancy of greater than 12 weeks
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × ULN or =< 5 x ULN (for subjects with documented metastatic disease to the liver)
• Creatinine clearance >= 30 mL/min (according to Cockcroft-Gault formula)
• Archived tumor specimen available for correlative analysis or biopsy accessible disease
• Detectable PD-L1 expression in tumor defined as combined positive score (CPS) >= 1
• Negative serum or urine pregnancy test for women of childbearing potential
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 60 days after final treatment on study. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Prior therapy with a PD-1 or PD-L1 inhibitor in the setting of recurrent or metastatic squamous cell carcinoma of the head and neck
• Chemotherapy within 28 days prior to first administration of study treatment and/or monoclonal antibody therapy within 8 weeks prior to the first administration of study treatment
• Uncontrolled central nervous system metastases. Stable, asymptomatic brain metastases not requiring escalating steroid doses are permitted
• Current use of immunosuppressive medication, EXCEPT for the following: * Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); * Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent; * Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
• Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
• Prior organ transplantation including allogenic stem-cell transplantation
• Active infection requiring systemic therapy
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
• Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV ribonucleic acid [RNA] if anti-HCV antibody screening test positive)
• Vaccination within 4 weeks of the first dose of pembrolizumab and while on trials is prohibited except for administration of inactivated vaccine
• As judged by the investigator, any evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease)
• History of significant hypotensive episode requiring hospitalization
• History of stroke within prior 6 months
• History of any of the following cardiac conditions: * 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 * 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 (New York Heart Association [NYHA] >= class II 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 solid organ transplantation
• Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE v 5.0] grade >= 3)
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 3 months prior to enrollment), unstable angina, congestive heart failure within 6 months of planned tadalafil administration (>= New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication
• Persisting toxicity related to prior therapy (NCI CTCAE v. 5.0 Grade > 1); however, alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety risk based on investigator’s judgment are acceptable
• Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
• History of other malignancies within the past three years, except: * Malignancy treated with curative intent and with no known active disease present for >= 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease
• Medical contraindication to biopsy of target lesion
• 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 other long-acting PDE5 inhibitors
• Known severe hypersensitivity to tadalafil or any of the excipients of this product
• Current treatment with nitrates
• Current treatment with guanylate cyclase stimulators such as riociguat
• Current systemic treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitor such as ketoconazole or ritonavir
• History of hypotension and/or blindness and/or sensorineural hearing loss during prior treatment with tadalafil or other PDE-5 inhibitors
• History of hereditary degenerative retinal disorders, including retinitis pigmentosa
• Use of alpha-blockers or alpha-adrenoreceptor antagonists
• Daily intake of 5 or more alcoholic drinks
• Prior history of non-arteritic anterior ischemic optic neuropathy