Phase 1b/II Trial of Pembrolizumab Plus IMRT in Stage III/IV Carcinoma of Anus

Inclusion Criteria: In order to be eligible for participation in this trial, the subject must: 1. Be willing and able to provide written informed consent/assent for the trial. 2. Age 18 years or over on day of signing informed consent. 3. Histologically proven Squamous Cell Cancer of Anus (SCCA) T3 / 4 N0 M0 or any N+ M0 or highly suspicious and confirmed by the MDT 4. Be willing to provide tissue sample either archival or repeat biopsy to be tested for HPV and p16. 5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 6. Demonstrate adequate organ function performed within 10 days of treatment initiation: 1. Hematological: Absolute neutrophil count (ANC) ≥1.5 x 109/L, Platelets ≥100 x 109/L, 2. Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants), Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants). 3. Renal: Serum creatinine ≤1.5 x upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥60 mL/min for patient with creatinine levels \> 1.5 x institutional ULN 4. Hepatic Serum total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 ULN 7. Female patient of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of trial medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 8. Female patients of childbearing potential must be willing to use an adequate method of contraception for the course of the trial through 120 days after the last dose of trial medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. 9. Male patients must agree to use an adequate method of contraception starting with the first dose of trial therapy through 120 days after the last dose of trial therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. Exclusion Criteria: The subject must be excluded from participating in the trial if the subject: 1. Has malignant tumour of non-epithelial origin (sarcoma) 2. Has any metastatic disease 3. Is unsuitable for radical CRT for whatever reason 4. Is currently participating and receiving trial therapy or has participated in a trial of an investigational agent and received trial therapy or used an investigational device within 4 weeks of the first dose of treatment. 5. Has a diagnosis of immunodeficiency (see 18. For patients with HIV who may be eligible) or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 6. Has a known history of active TB (Bacillus Tuberculosis) 7. Hypersensitivity to pembrolizumab or any of its excipients. 8. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 1. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. 2. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 10. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or previous VIN (vulval intra-epithelial neoplasia) or vulval cancer adequately treated, or previous adequately treated breast cancer / DCIS \> 5 years ago. 11. 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 (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 12. Has known history of, or any evidence of active, non-infectious pneumonitis. 13. Has an active infection requiring systemic therapy. 14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g. HCV RNA is detected). Testing only required if patient has a history of either of these. 20. Has received a live vaccine within 30 days of planned start of study therapy. (Note: 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.)