The ARTEMIS trial is for patients who have been diagnosed as having a cancer of the lower bowel, known as the rectum. This study will examine the benefit of adding an additional treatment alongside radiotherapy and chemotherapy with the hope of increasing the chance of curing rectal cancer without the need for surgery.

INTERVENTION: Radiotherapy: All patients will receive standard radiotherapy delivered using Intensity modulated radiotherapy (IMRT), Volumetric‐modulated arc therapy (VMAT) or TomoTherapy to treat an elective pelvic clinical target volume (CTV) to one of two standard regimens (clinician choice on an individual patient basis). 1) Long‐course chemoradiation (LCCRT) ‐ 45Gy in 25 daily fractions treating once per day Monday‐Friday over 5 weeks, with a synchronous integrated small volume boost to the gross tumour volume (GTV) of 50Gy in 25 fractions. Concurrent capecitabine will be given on the days of radiotherapy orally at 825mg/m2 twice daily (BID) throughout the radiotherapy course. 2) Short‐course radiotherapy (SCRT) ‐ 25Gy in 5 daily fractions treating once per day Monday‐Friday over 5 days (without concurrent chemotherapy). Chemotherapy: All patients will receive 12 weeks of FOLFO Xor CAPO Xstarting 3 weeks after the last radiotherapy treatment (clinical choice on a patient‐by‐patient basis). Participants will be randomised (1:1) intervention to control arm. Control Arm: LCCRT or SCRT followed by FOLFO Xor CAPOX. Intervention Arm: LCCRT or SCRT followed by FOLFO Xor CAPO Xwith the addition of immunotherapy agent, AN0025. AN0025 is given orally at a dose of 500mg once a day (QD) continuously, 7 days a week starting two weeks before SCRT/LCCRT and continuing until the end of the 12 week course of FOLFOX/CAPOX. 1) LCCRT ‐ AN0025 starts 14 days prior to start of LCCRT and continues for 22 weeks*, QD, 7 days per week. 2) SCRT ‐ AN0025 starts 14 days prior to start of SCRT and continues for 18 weeks*, QD, 7 days per week. CONDITION: Locally advanced rectal cancer ; Cancer PRIMARY OUTCOME: ; Clinical complete response (cCR) rate at 6 months post‐start of treatment assessed via a composite of digital rectal examination (DRE), high resolution pelvic Magnetic Resonance Imaging (MRI) and sigmoidoscopy, defined as:; 1. No evidence of either mucosal tumour or submucosal swelling on white light endoscopy. A flat white scar remains, with or without telangiectasia or a small residual mucosal ulcer and; 2. No palpable tumour upon DRE, and; 3. High resolution pelvic MRI scanning shows complete response in both the primary tumour and involved nodes (participants on active surveillance who do not undergo surgery).; (If the tumour is too proximal to reach with DRE then assessment will be via MRI and sigmoidoscopy alone).; SECONDARY OUTCOME: ; 1. Acute & Late toxicity:; The acute toxicity period has been defined from randomisation (AN0025 or RT) to the 6 month post start of RT primary endpoint assessment. Clinician assessment of acute toxicities will take place on each week of treatment during clinic, including the 4 and 6 month follow‐up assessments. The late toxicity period will be defined as 6 months post‐start of RT until the final follow‐up visit at 30 months post start of RT. Clinician assessment of late toxicity will take place during each of the follow‐up visits and will be recorded at 9, 12, 18, 24 and 30 months post start of RT.; All adverse events will be evaluated using the CTCAE criteria (V5.0) and include all AEs, SAEs, ARs, SARs and SUSARs. The CTCAE criteria will only be used and collected prior to patients receiving surgery.; 2. Treatment compliance:; Data on the treatment which participants receive will be collected weekly during radiotherapy and during weeks of chemotherapy. Compliance to the treatment will be assessed and include adherence to both the radiotherapy, chemotherapy, and if received AN0025.; Information will be recorded on the total dose of radiotherapy received (dose and fractions), the overall treatment time (i.e., start and end date), details of any interruptions to the radiotherapy and the reasons for these interruptions (i.e., toxicity or other). Chemotherapy treatment compliance data will be recorded on the number of cycles received, any treatment modifications, including delays, omissions or reductions, and their associated reasons. Details of any dose reductions or omissions of AN0025 and associated reasons for participants in the intervention arm will also be recorded.; Adherence to the radiotherapy schedule will be defined as a participant that has completed their scheduled course of radiotherapy with no more than three treatment days of interruptions due to toxicity. Adherence to the chemotherapy and AN0025 will be defined as a participant that completes > 80% of the original prescribed dose.; 3. Patient reported outcomes (PROs) and Health Related Quality of Life (HRQoL):; PRO and HRQoL data will be captured via the EORTC QLQ‐C30, QLQ‐CR29, EQ‐5D‐5L and LARS questionnaires, and additional items relevant to an organ sparing approach to treatment using the EORTC‐QLQ item library. HRQoL will be requested at baseline, 3 weeks post end of RT, and 4, 6, 12, 24 and 30 months post‐start of RT treatment. PRO results will describe the treatment impact on patient experience over the course of the study. The goal of the PRO assessment is to assess tolerability from the patient's perspective; i.e., how patients are feeling and functioning (descriptive objective), encompassing both early and late effects. To ensure high quality data and interpretation, PRO data will be implemented and analysed using international consensus guidelines. The data will capture early effects of treatment, and long term patient experience.; 4. Surgical outcomes:; Details on any surgery performed will be collected including the type, approach and outcome (residual tumour R classification). Post‐surgical outcomes will also be collected including length of hospital stay, surgical complications measured by the Clavien Dindo classification system 90 days post‐operatively, and any reoperation details where appropriate.; 5. Response assessment:; Local control data will be collected for all patients. Assessments of cCR and mrTRG will be collected in patients on active surveillance at 4, 6, 9, 12 months post start of RT. Continued cCR confirmation will be collected at 18, 24, 30 month post start of RT.; A pathological Complete Response (pCR) is defined as the absence of any viable tumour cell on the resected specimen, irrespective of the proportion of necrosis and fibrosis (Quah et al., 2008). The five point Mandard Tumour Regression Grade (TRG) (Mandard et al., 1994) is a measure of histopathological response of rectal cancer and will be assessed in patients after surgery in addition to the current standard of care four point AJCC Tumour Regression Score system. pCR TRG and TRS will be assessed once after surgery.; 6. Stoma rates:; Stoma data will be collected at standard follow‐up visits. Date of stoma formation, type of stoma and reason for defunctioning will be collected. Stoma rates will be presented and analysed as a time‐to‐event outcome i.e., the time from randomisation to the fashioning of a stoma.; 7. Locoregional regrowth after cCR:; Locoregional regrowth is defined as the detection of a tumour involving either the bowel wall, mesorectum or pelvic organs that occurs after an initial cCR. Date of confirmed regrowth will be collected.; 8. Organ preservation rates:; Organ preservation in the setting of ARTEMIS is defined by intact rectum, absence of stoma and free of locoregional failure. Where locoregional failure is detection of any un‐resectable regrowth or recurrence involving either the bowel wall, mesorectum and/or pelvic organs. Data on surgery, stomas and locoregional disease will be collected on all patients. Organ preservation rates will be assessed over time.; 9. Organ‐preservation‐adapted Disease‐free survival:; Organ‐preservation‐adapted Disease free survival (OP‐DFS) is defined as the time from randomisation, to the first confirmed evidence of un‐resectable regrowth or locoregional recurrence after TME, any distant metastasis, any second primary cancer (including non‐colorectal) or death from any cause. First confirmed evidence can include imaging, histology or endoscopy.; 10. Metastasis free survival:; Metastasis free survival (MFS) is defined as the time from randomisation, to the first confirmed INCLUSION CRITERIA: 1. Patients age =18 years old 2. ECOG PS 0 or 1 3. Capable of informed consent 4. Able to fully understand trial treatment enough to provide informed consent 5. Biopsy‐proven rectal adenocarcinoma 6. Staged on high‐resolution MRI as: T3b‐4a or TanyN1‐2 or TanyEMVI+ or with a threatened (<1mm) or involved mesorectal fascia resection margin or breached but not invading other organs or definite pelvic side wall lymph nodes involved (that the MDT feel are not resectable) 7. Low tumours with involvement of the anal intersphincteric plane or with levator involvement. The superior extent of macroscopic tumour (primary, EMVI or nodes) is no higher than the S1/2 junction on sagittal MRI. Within 14 days pre‐randomisation the following must be met: 8. Estimated creatinine clearance =50 mls/min (using a validated creatinine clearance calculation e.g. Cockcroft‐Gault or Wright formula) 9. Haemoglobin = 9.