NEOadjuvant PembRolizumab In Stratified Medicine - ColoRectal Cancer

Inclusion Criteria:

1. Histologically proven adenocarcinoma of the colon or rectum which is MMR-d by IHC orMSI-H by PCR (or microsatellite testing if routine practice).

2. Patient is fit (ECOG 0-1) and eligible for planned curative surgery in keeping withNICE guidelines and considered fit/suitable for adjuvant chemotherapy as per localsite investigator's discretion based on:

3. Radiological node positive T1-4 CRC or

4. Node negative high risk T3 defined as EITHER ≥ 5mm of extramural depth ofinvasion OR unequivocal EMVI on imaging (regardless of depth) or Node negativeT4 disease

5. Patients with rectal cancer are eligible if it is determined that neoadjuvantchemo-radiotherapy is not required to achieve a R0 resection.

6. Patients presenting with acute colonic obstruction may enter the trial only afterobstruction is relieved by a successful defunctioning stoma/stent, and whenrecovered to a fitness level consistent with the other eligibility criteria

7. Adequate bone marrow function:

• White Blood Cell >3.0 x 10^9/L;

• Absolute neutrophil count ≥1.5 x 10^9/L

• Platelets ≥100 x 10^9/L.

• Haemoglobin ≥90 g/L

6. Adequate renal function: GFR >50 mL/min estimated using validated creatinine clearance calculation (e.g.Cockroft-Gault) NB If the calculated creatinine clearance is < 50 mL/min, a formal 24 hour urine collection or isotope clearance must be carried out demonstrating GFR ≥ 50 mL/min as per institutional standards

7. Adequate liver function: Total bilirubin < 1.5 times Upper Limit of Normal (ULN) OR direct bilirubin ≤ULN forparticipants with total bilirubin levels >1.5 × ULN AST and ALT ≤ 2.5 × ULN

8. Adequate coagulation: International normalized ratio (INR) OR prothrombin time (PT) and Activated partialthromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulanttherapy as long as PT or aPTT is within therapeutic range of intended use ofanticoagulants

9. Aged ≥18 years

10. Able and willing to provide written informed consent

11. Female patients of child bearing potential must be willing to use highly effectivecontraception for the duration of trial treatment and for 120 days after last doseof pembrolizumab

Exclusion Criteria:

1. Any patient for whom radiotherapy is advised by the MDT

2. Strong evidence of distant metastases or peritoneal nodules (M1)

3. Prior therapy with an anti-PD-1, anti-PD-L1 or anti-PD-L2 agent, or with an agentdirected to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4,OX-40, CD137)

4. Prior systemic anti-cancer therapy including investigational agents within 4 weeksprior to registration.

(NB: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline, with the exception of alopecia. Participants with ≤Grade 2neuropathy may be eligible.) (NB: If participant received major surgery, they musthave recovered adequately from the toxicity and/or complications from theintervention prior to starting study treatment.)

5. Has received a live vaccine or live-attenuated vaccine within 30 days prior toregistration (seasonal flu vaccines that do not contain live virus are permitted).Administration of killed vaccines is allowed

6. Any investigational agents or investigational devices within 4 weeks prior toregistration Note: Participants who have entered the follow-up phase of aninvestigational study may participate as long as it has been 4 weeks after the lastdose of the previous investigational agent.

7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10mg daily of prednisolone or equivalent), or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of trial treatmentNote: the use of physiologic doses of corticosteroids may be approved afterconsultation with UCL CTC.

8. Patients with concurrent or previous malignancy that could compromise assessment ofthe primary or secondary endpoints of the trial

9. Has known active CNS metastases and/or carcinomatous meningitis.

10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or to any of itsexcipients.

11. Has previous severe or life-threatening skin adverse reaction with otherimmune-stimulatory anticancer agents

12. Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). NB: Replacement therapy (e.g. levothyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is permitted.

13. History of (non-infectious) pneumonitis/interstitial lung disease that requiredsteroids, or current pneumonitis/interstitial lung disease

14. Active infection requiring systemic therapy

15. Known history of Human Immunodeficiency Virus (HIV). NB: Testing for HIV for theNEOPRISM-CRC trial is not mandatory, however if this test has been done the resultshould be known prior to registration.

16. Known active infection for hepatitis B (hepatitis B surface antigen [HbsAg]reactive) or known active hepatitis C (defined as hepatitis C virus [HCV] RNA [qualitative] is detected)

• Testing is required to determine eligibility. Hepatitis C antibody testing isallowed for initial screening purposes in sites where HCV RNA is not part ofstandard of care.

• Patients who are HbsAg positive are eligible if they have received HBVantiviral therapy for at least 4 weeks and have undetectable HBV viral loadprior to registration. Participants should remain on anti-viral therapythroughout trial treatment and follow local guidelines for HBV anti-viraltherapy post completion of trial treatment.

• Patients with history of HCV infection are eligible if HCV viral load isundetectable at screening and have completed anti-viral therapy at least 4weeks prior to registration.

17. Known history of active TB (Mycobacterium tuberculosis).

18. Has had an allogenic tissue/solid organ transplant.

19. Has peritonitis (secondary to perforated tumour)

20. Has a colonic obstruction that has not been defunctioned or stented

21. History or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the study, interfere with the subject'sparticipation for the full duration of the study, or is not in the best interest ofthe subject to participate, in the opinion of the treating investigator.

22. Known psychiatric or substance abuse disorder that would interfere with theparticipant's ability to cooperate with the requirements of the study.

23. Female patients of child bearing potential who is pregnant or breastfeeding, orexpecting to conceive within the projected duration of the trial, starting with thepre-screening or screening visit through 120 days after the last dose ofpembrolizumab