A Study of ASP-1929 Photoimmunotherapy in Combination With Pembrolizumab in First-line Treatment of Locoregional Recurrent Squamous Cell Carcinoma of the Head and Neck With No Distant Metastases

Inclusion Criteria: * Histological or cytological evidence of squamous cell carcinoma of a head and neck primary site (per American Joint Committee on Cancer \[AJCC\], other than nasopharynx or cuSCC). * Appropriate for SOC first-line treatment of their recurrent head and neck cancer with pembrolizumab ± chemotherapy. * No known history of any distant metastatic disease (M1 by AJCC eighth edition). * Tumors with at least one PIT-accessible and RECIST 1.1 measurable lesion as assessed by investigator. * Anti-PD-1 and anti-PD-L1-treatment naïve. * Combined positive score (CPS) ≥ 1 as determined locally by an FDA-approved test * Have results from testing of human papillomavirus (HPV) status for oropharyngeal cancer * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at the time of screening * Adequate hematologic, renal, and hepatic organ function * Women of childbearing potential (WOCBP) must have a negative pregnancy test at screening and must be willing to use a highly effective birth control while on study or be surgically sterile or abstain from heterosexual sexual activity for the course of the study through 180 days after the last dose of study treatment. Male patients must agree to use a highly effective method of contraception starting with the first dose of study medication through 120 days after the last dose of study treatment. Exclusion Criteria: * Diagnosed and/or treated for additional malignancy within 2 years before randomization except for those with a negligible risk of metastasis or death (such as adequately treated carcinoma in situ of the cervix, basal cell skin cancer, localized prostate cancer, or ductal carcinoma in situ). Patients with a history of other prior cancer treated with complete surgical resection and with no evidence of disease may be eligible based on discussion with the Medical Monitor. * History of significant (Grade ≥ 3) cetuximab infusion reactions * Prior allogeneic tissue/solid organ transplant * Known or active central nervous system metastases and/or carcinomatous meningitis * Life expectancy of less than 3 months * Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. * Evidence of interstitial lung disease or current active, noninfectious pneumonitis * Active infection requiring systemic therapies such as antibiotic, antifungal, or antiviral intervention * Known or active bacterial, viral, or fungal infection including tuberculosis, Hepatitis B (e.g., HBV DNA is detected), or Hepatitis C (e.g., RNA \[qualitative\] is detected) * Known history of testing positive for human immunodeficiency virus or acquired immunodeficiency syndrome (AIDS)-related illness * Prior or ongoing Grade ≥ 3 tumor hemorrhage within 12 weeks of randomization * Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Prior systemic chemotherapy or targeted small molecule therapy or radiation therapy within 2 weeks of C1D1 or has not recovered (i.e., Grade ≤ 1 or at baseline) from adverse events (AEs) due to previously administered agent * Prior anticancer monoclonal antibody therapy or investigational agent or intervention within 4 weeks of C1D1 or has not recovered (i.e., Grade ≤ 1 or at baseline) from AEs due to previously administered agent * Prior receipt of ASP-1929 at any time * Receiving chronic systemic steroid therapy (in doses exceeding 10 mg per day of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior to randomization * Received a live vaccine within 4 weeks of randomization; seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed * Requiring future examinations or treatments within 4 weeks after an ASP-1929 PIT treatment exposing the patient to significant light (e.g., eye examinations, surgical procedures, endoscopy) that is unrelated to the ASP-1929 PIT treatment * Major surgery or significant traumatic injury within 4 weeks before randomization, or anticipation of the need for major surgery during the course of study treatment