Molecular Residual Disease Interception in Locoregionally-Advanced High Risk HPV+ and HPV- HNSCC

Inclusion Criteria for All Parts 1. Age ≥ 18 years at the time of screening or age of consent according to law. 2. Written informed consent and any locally required authorization (e.g., data privacy) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 4. Weight ≥ 35 kg. 5. Must have a life expectancy of at least 12 weeks. 6. Histological or cytological confirmed LA-HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx. Patients with locoregionally advanced unknown head and neck primary but tumor tested to be p16-positive are eligible. 7. High-risk HPV negative LA-HNSCC patients (stage III-IVB according to AJCC/UICC 8th Edition) OR high-risk HPV positive LA-HNSCC patients (stage III according to AJCC/UICC 8th Edition). 8. Archival tumor formalin-fixed, paraffin-embedded (FFPE) specimens for correlative biomarker studies are required (1 H\&E and 10 unstained 5 microns slides). If surgery is going to be performed after signing consent, then tumor FFPE from that surgery is allowed. 9. Patient is a candidate for definitive treatment: either surgery followed by radiation or chemoradiation, OR definitive radiation, OR definitive chemoradiation. Inclusion Criteria for Part C 10. Objective radiological tumor response according to CT or MRI at 8-12 weeks after definitive therapy (surgery followed by radiation or chemoradiation, OR definite radiation, OR definite chemoradiation) 11. ECOG performance status of 0 or 1 at randomization. 12. Tumor must express PD-L1 (CPS ≥1) as determined by the local laboratory using the PD-L1 IHC 22C3 pharmDx assay. 13. Detection of ctDNA in plasma samples collected in Part B in either: 1. both samples collected at approximately week 5 (4-6) and at week 10 (8-12) OR 2. only in the week 10 (8-12) sample NOTE: If ctDNA results at Week 10 are equivocal, a new sample should be collected and analyzed to confirm results within 4 weeks. 14. Adequate organ and marrow functions as defined in Table 4.Table 4 (4.1.2-2): Criteria for Adequate Organ and Marrow Function Parameter Value Hematological Hemoglobin ≥ 9 g/dL Absolute neutrophil count ≥ 1,500 µ/L Platelet count ≥ 100,000 µ/L Hepatic- Total bilirubin ≤ 1.5 × ULN * 3 × ULN is allowed in the presence of documented Gilbert's syndrome Alanine transaminase and Aspartate transaminase ≤ 3 × ULN Renal Serum creatinine or Calculated creatinine clearance Serum creatinine \< 1.5 x ULN or CrCl ≥ 40 mL/minute ULN = upper limit normal. a Hematological criteria cannot be met with ongoing or recent blood transfusions (within 28 days prior to the scheduled first dose of study treatment) or require growth factor support (within 21 days prior to the scheduled first dose of study treatment). b As determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance. 15. Body mass index ≥ 17. 16. Females of childbearing potential who are sexually active with a nonsterilized male partner must use at least one highly effective method of contraception (see Section 8.1.1 for definition of females of childbearing potential and for a description of highly effective methods of contraception) from screening to 4 months after the final dose of study treatment. It is strongly recommended for the male partner of a female subject to also use male condom plus spermicide throughout this period. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. 17. Nonsterilized male subjects who are sexually active with a female partner of childbearing potential must use a male condom with spermicide from screening to 4 months after receipt of the final dose of study treatment. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. It is strongly recommended for the female partner of a male subject to also use a highly effective method of contraception throughout this period, as described in Section 8.1.2. In addition, male subjects must refrain from sperm donation while on study and for 4 months after the final dose of study treatment. Inclusion Criteria for Part E 18. Objective radiological tumor response according to CT or MRI at 8-12 weeks after definitive therapy (surgery followed by radiation or chemoradiation, OR definitive radiation, OR definitive chemoradiation) 19. No detection of ctDNA in plasma samples analysed in the week 10 (8-12) sample collected in Part B. Exclusion Criteria Any of the following would exclude the subject from participation in the study: 20. Histological or cytologically confirmed head and neck cancer of any other primary anatomic location in the head and neck not specified in the inclusion criteria including participants with p16-negative squamous cell carcinoma of unknown primary or non-squamous histologies (eg, nasopharynx, paranasal sinus or salivary gland). 21. Any unresolved toxicity NCI CTCAE ≥ Grade 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with AZD2936 may be included only after consultation with the Principal Investigator. 22. Evidence of distant metastasis in staging. 23. History of allogeneic organ transplantation. 24. History of allergic reactions or hypersensitivity attributed to compounds of similar chemical or biologic composition to AZD2936 or any of the excipients. 25. History of active primary immunodeficiency. 26. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], immune related diverticulitis \[prior diverticulitis in the context of diverticulosis is allowed provided is not active\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion: 1. Participants with vitiligo or alopecia 2. Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement 3. Any chronic skin condition that does not require systemic therapy. Participants without active disease in the last 5 years may be included but only after consultation with the Principal Investigator 4. Participants with celiac disease controlled by diet alone 27. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive HBV surface antigen \[HBsAg\] result), or hepatitis C(HCV) or acute hepatitis A. Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Also participants who have chronic hepatitis B and are receiving suppressive antiviral therapy are allowed to be enrolled if ALT is normal and viral load is controlled (\<100 U/ml by polymerase chain reaction). These patients must remain on antiviral therapy as per institutional practice during the study treatment and follow up period to ensure adequate viral suppression. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 28. Patients with a known history of infection with human immunodeficiency virus (positive HIV 1/2 antibodies) are excluded. Testing in patients with no known history or no known risk factors is not required. 29. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months or high risk of uncontrolled arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent. 30. History of another primary malignancy except for: 1. Malignancy treated with curative intent and with no known active disease ≥ 2 years before the first dose of study treatment and of low potential risk for recurrence 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease 3. Adequately treated carcinoma in situ without evidence of disease 4. Participants with a history of prostate cancer (tumor/node/metastasis stage) of Stage ≤ T2cN0M0 without biochemical recurrence or progression and who in the opinion of the investigator are not deemed to require active intervention. Prior/Concomitant Therapy 31. Any concurrent anticancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is allowed. 32. Prior AZD2936 therapy, anti-PD-1/L1 or TIGIT antibody. 33. Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention. The following are exceptions to this criterion (see Section 4.7.1 1. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection) 2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent 3. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) 34. Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live vaccine whilst receiving study intervention and up to 30 days after the last dose of study intervention. COVID 19 vaccination should not be given for 72 hours prior to administration of the first dose of AZD2936. Prior/Concurrent Clinical Study Experience 35. Participation in another clinical study with an investigational product administered in the last 28 days prior to randomization or concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. Other Exclusions 36. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements. 37. For women only - currently pregnant (confirmed with positive pregnancy test) or breastfeeding. 38. Females who are pregnant, lactating, or intend to become pregnant during their participation in the study. 39. Subjects who are involuntarily incarcerated or are unable to willingly provide consent or are unable to comply with the protocol procedures.