tadalafil and pembrolizumab in recurrent or metastatic head and neck cancer

Conditions: 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

Summary: 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.

Eligibility criteria:
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).

Keywords: cancer pembrolizumab tadalafil cialis opdivo immunotherapy metastatic carcinoma pd-1 pde