SBRT and Evorpacept with Pembrolizumab before Surgery for the Treatment of Stage I HPV Mediated Oropharyngeal Cancer

Inclusion Criteria

• Patient has the ability to understand and the willingness to sign a written informed consent
• Histologically confirmed diagnosis of previously untreated American Joint Committee on Cancer (AJCC) VIII stage I T1-2N1M0 HPV mediated oropharynx cancer amenable to surgical resection who are able to safely receive neoadjuvant radiation and evorpacept/pembrolizumab, excluding patients with solitary lymph nodes less than 3 cm. Patients must undergo HPV testing by p16 immunohistochemistry (IHC) as by convention to confirm HPVOPC
• Have provided archival tumor tissue sample collected within the last 6 months or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin- fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Note: If submitting unstained slides, slides should be submitted to the testing laboratory within 14 days from the date slides are cut
• Patient is ≥ 18 years of age
• Both men and women of all races and ethnic groups are eligible for this trial
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Evaluation of ECOG performance status is to be performed within 14 days prior to the date of enrollment
• Absolute neutrophil count: ≥ 1.5 x 10^9/L (within 42 days prior to treatment initiation)
• Platelet count: ≥ 100 x 10^9/L (within 42 days prior to treatment initiation)
• Hemoglobin: ≥ 9.0 g/dL (within 42 days prior to treatment initiation) Hemoglobin threshold must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be on stable doses of erythropoietin (≥ approximately 3 months)
• Total bilirubin: ≤ 1.5 x institution's upper limit of normal (ULN) (within 42 days prior to treatment initiation)
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SPGT): ≤ 2.5 x institutional upper limit of normal (within 42 days prior to treatment initiation)
• Serum creatinine: ≤ 1.5 x institution's ULN or ≥ 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (within 42 days prior to treatment initiation)
• International normalized ratio (INR) or prothrombin time (PT), activated partial thromboplastin time (aPTT): ≤ 1.5 x ULN (within 42 days prior to treatment initiation) (unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants)
• Women of child-bearing potential and men with partners of child-bearing potential 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 120 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• Women of child-bearing potential has negative pregnancy test within 72 hours prior to initiating radiation

Exclusion Criteria

• Patient is current receiving or has received another investigational agent within 4 weeks prior to study treatment initiation
• Has received any prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137), or has received any prior therapy with an anti-CD47 agent or anti-SIRPα agent
• Has severe hypersensitivity (≥ grade 3) to pembrolizumab, anti-CD47 agent or anti-SIRPα agents, and/or any of their excipients
• Has received prior radiotherapy to the head and neck region
• Patients in whom adjuvant chemoradiation would be recommended regardless of response to the study treatment as determined by treating physicians
• Any of the following in the previous 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class II or greater congestive heart failure, cerebrovascular accident, or transient ischemic attack, deep venous thrombosis, arterial thrombosis, symptomatic pulmonary embolism, or any other significant thromboembolism. Any major surgery within 28 days prior to enrollment
• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) or other solid tumor or hematologic malignancy that have undergone potentially curative therapy outside of the head and neck are not excluded from enrollment
• Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• History of autoimmune hemolytic anemia, autoimmune thrombocytopenia, or hemolytic transfusion reaction
• Has had experimental antibodies or live vaccines in the last 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette-Guerrin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
• Has active, uncontrolled, clinically significant bacterial, fungal, or viral infection requiring systemic therapy, including hepatitis B (HBV), hepatitis C (HCV), known infection with SARS-CoV-2, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness * If has a known history of human immunodeficiency virus (HIV) testing is not required unless mandated by local health authority * If has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA]) infection. Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority * If has a known history of active TB (bacillus tuberculosis). Testing is not required unless mandated by local health authority
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
• Patients with prior history of solid organ and/or allo-transplantation
• Patients with pre-existing neuropathy of grade 2 or higher peripheral neuropathy
• Patient has a severe or uncontrolled medical disorder that would, in the investigator’s opinion, impair ability to receive study treatment (i.e., uncontrolled diabetes, chronic renal disease, chronic pulmonary disease or active, uncontrolled infection, psychiatric illness/social situations that would limit compliance with study requirements)