Tadalafil and Pembrolizumab in Recurrent or Metastatic 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.

• Pembrolizumab (Drug), also known as Keytruda: 200 mg intravenously every 3 weeks
• Tadalafil (Drug), also known as Cialis: 10 mg by mouth daily

Primary outcomes

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

Secondary outcomes

• Response Measured by RECIST 1.1 [12 months]: Response measured by RECIST 1.1
• Progression Free Survival [2 years]: Progression free survival
• Adverse Event Rates [2 years]: Adverse event rates

Sex: All, ages: 18 Years to any

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).

Participant flow

Outcome results

• Rate of Dose Limiting Toxicity (DLT) (Primary), Count of participants, Participants: Tadalafil and Pembrolizumab 1
• Overall Survival (OS) (Primary), Count of participants, Participants: Tadalafil and Pembrolizumab 3
• Response Measured by RECIST 1.1 (Secondary), Count of participants, Participants: Tadalafil and Pembrolizumab 1
• Progression Free Survival (Secondary), Mean, months: Tadalafil and Pembrolizumab 21.56 +/- 22.98
• Adverse Event Rates (Secondary), Count of participants, Participants: Tadalafil and Pembrolizumab 6

Adverse events

Time frame: 2 years

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2020-05-05)

• Joseph Califano, Principal investigator, UCSD