Phase II Trial of Magrolimab and Cetuximab With Pembrolizumab or Docetaxel for Recurrent/Metastatic Head Neck Squamous Cell Carcinoma

Inclusion Criteria: All patients must meet all of the following inclusion criteria to be eligible for participation in this study: 1. Patient must have a diagnosis of recurrent or metastatic oropharynx, oral cavity, hypopharynx, or larynx squamous cell carcinoma (HNSCC), not amenable to curative-intent local therapy with known PD-L1 CPS determined by an FDA-approved test. Patients with unknown primary squamous cell carcinoma presumed from the head and neck are also eligible upon discussion with study principal investigator. 2. Patient has provided informed consent. 3. Patient is willing and able to comply with clinic visits and procedures outlined in the study protocol. 4. Male or female ≥ 18 years of age 5. ECOG performance status of 0 or 1 6. Laboratory measurements, blood counts: 1. Hemoglobin ≥ 9 g/dL within 24 hours prior to initial dose of study treatment. Red blood cell transfusions are permitted to meet the hemoglobin inclusion criteria, within limits set per exclusion criterion 6. 2. Absolute neutrophil count ≥ 1.2 x 109/mL 3. Platelets ≥ 100 x 109/mL 7. Laboratory measurements, renal function: Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or if elevated, a calculated glomerular filtration rate \> 40 mL/min/1.73m2 per CKD-EPI equation. 8. Laboratory measurements, hepatic function: 1. AST and ALT ≤ 2.5 x ULN or ≤ 5 x ULN in patients with liver metastases 2. Total bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN and primarily unconjugated if patient has a documented history of Gilbert's syndrome or genetic equivalent 9. Laboratory measurements, coagulation function: 1. International normalized ratio or prothrombin time (PT) ≤ 1.5 x ULN unless patient is receiving anticoagulation therapy, as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use for anticoagulants 2. Activated partial thromboplastin time or PTT ≤ 1.5 x ULN unless patient is receiving anticoagulation therapy, as long as PT or PTT is within therapeutic range of intended use for anticoagulants 10. Female patients with reproductive potential must practice two effective contraceptive measures for the duration of study drug therapy and for at least 6 months after completion of study therapy. The two birth control methods can be either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. The following are considered adequate barrier methods of contraception: diaphragm, condom, copper intrauterine device, sponge, or spermicide. Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 11. Male patients who are sexually active with women with reproductive potential must agree to use contraception for the duration of treatment and for at least 6 months after completion of study therapy. 12. Measurable disease according to RECIST, version 1.1 13. Patients must be willing to provide baseline tumor tissue from a core or excisional biopsy (fine needle aspirate is not adequate). A newly obtained biopsy (within 90 days prior to study treatment start) is strongly preferred, but an archival sample is acceptable. 14. Absence of active auto-immune disease or any other contra-indication to pembrolizumab, cetuximab, docetaxel or magrolimab Cohort A: In addition to meeting the inclusion criteria for all patients, patients who are enrolled into Cohort A must fulfill the following cohort-specific inclusion criteria: 15. PD-L1 CPS must be ≥ 1 16. Patients should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy that was completed more than 3 months prior to signing consent if given as part of multimodal treatment for locally advanced disease is allowed. 17. Patients could have received anti-PD1 or anti-PD-L1 in the neoadjuvant or adjuvant setting as part of a clinical trial, as long as the patient has not progressed during it and there has been at least a 6 months disease-free interval since last administration of anti-PD1 or anti-PD-L1 in the curative intent setting. Cohort B: In addition to meeting the inclusion criteria for all patients, patients who are enrolled into Cohort B must fulfill the following cohort-specific inclusion criterion: 17\) Patients must have received at least 1 and no more than 2 lines of prior systemic anticancer therapy in the recurrent/metastatic setting not including docetaxel but including anti-PD1. Patients must have progressed on anti-PD1 (radiographically or clinically) or developed intolerable adverse events attributed to anti-PD1 that lead to treatment discontinuation and eventual disease progression. Patients with contra-indications to anti-PD1 are also eligible. Exclusion Criteria: Patients who meet any of the following exclusion criteria are not eligible to be enrolled in this study: 1. Prior radiation therapy (or other nonsystemic therapy) within 2 weeks prior to enrollment 2. Patient has not fully recovered (ie, ≤ Grade 1 at baseline) from AEs due to a previously administered treatment. 1. Note: Patients with ≤ Grade 2 neuropathy, alopecia, or laboratory values in inclusion criteria 5 through 8 are exceptions to this criterion and may qualify for the study. 2. Note: If a patient received major surgery, he or she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 3. Active CNS disease (patients with asymptomatic and stable, treated CNS lesions who have been off corticosteroids, radiation, or other CNS-directed therapy for at least 4 weeks are not considered active) 4. Red blood cell transfusion dependence, defined as requiring more than 2 units of packed RBC transfusions during the 4-week period prior to screening. Red blood cell transfusions are permitted during the screening period and prior to enrollment to meet the hemoglobin inclusion criterion. 5. History of hemolytic anemia, autoimmune thrombocytopenia, or Evans syndrome in the last 3 months 6. Known inherited or acquired bleeding disorders 7. Prior treatment with CD47 or SIRPα-targeting agents 8. Prior anticancer therapy including, but not limited to, chemotherapy, immunotherapy, or investigational agents within 4 weeks prior to magrolimab treatment 9. Life expectancy of less than 3 months and/or rapidly progressing disease (eg, tumor bleeding, uncontrolled tumor pain) in the opinion of the treating investigator 10. Diagnosis of immunodeficiency or receipt of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study therapy. Corticosteroid use as a premedication for biopsy, allergic reactions or for prophylactic management of AEs related to the chemotherapies specified in the protocol is allowed. The use of physiologic doses of corticosteroids may be approved with approval by the sponsor. 11. Active autoimmune disease that has required systemic treatment in the past 2 years (ie, use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. 12. Prior allogeneic tissue/solid organ transplant 13. Current participation in another interventional clinical study 14. History of previous malignancy other than malignancy treated with curative intent and with no evidence of active disease ≥ 2 years before the first dose of the study drugs and of low potential risk for recurrence. Patients with the following diagnoses represents an exception and may enroll: 1. Non-melanoma skin cancers with no current evidence of disease 2. Melanoma in situ with no current evidence of disease 3. Localized cancer of the prostate with prostate-specific antigen of \<1 ng/mL 4. Treated or localized well-differentiated thyroid cancer 5. Treated cervical carcinoma in situ 6. Treated ductal/lobular carcinoma in situ of the breast 15. Evidence of uncontrolled, active infection, requiring systemic anti-bacterial, anti-viral or anti-fungal therapy ≤ 10 days prior to administration of investigational product. Patients with known hepatitis B, hepatitis C (HCV), or HIV infection could go on study provided the viral load is undetectable at Screening. 16. Significant disease or medical conditions, as assessed by the investigator and sponsor, that would substantially increase the risk-benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III-IV 17. Female subjects who are pregnant or breast-feeding 18. Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient