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.

Phase 2

• Conditions: ocally advanced rectal cancer; Cancer

• Registration Number: ISRCTN15384496
• Lead Sponsor: niversity of Leeds

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-10-23
• Last Update Posted: 8 July 2024
• Study Completion: 2028-05-31

Recruitment & Eligibility

• Status: Ongoing
• Sex: All
• Target Recruitment: 140

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 = 9.0g/dL
10. Neutrophils >1.5 x 10^9/l
11. Platelets >100 x 10^9/l
12. Adequate blood coagulation function as evidenced by a prothrombin time (PT) <1.5 x normal
13. Alkaline phosphatase (ALP) = 2.5 × upper limit of normal (ULN)
14. Serum transaminase (either alanine aminotransferase (ALT) or aspartate aminotransferase (AST)) = 2.5 × ULN
15. Total bilirubin =1.5 × ULN except for unconjugated hyperbilirubinemia or Gilbert’s syndrome

Exclusion Criteria

1. Unequivocal distant metastatic disease
2. Previous pelvic radiotherapy
3. MRI defined predominantly mucinous tumour i.e. more than one third of tumour volume assessed to consist of mucin
4. Biopsy-proven neuroendocrine tumour
5. Definite MRI pelvic side wall lymph node involvement, invasion of adjacent organ, ischio-rectal fossa involvement
6. Pre-existing faecal incontinence for solid stool or chronic diarrhoea (> grade 1 according the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE))
7. Defunctioning colostomy or ileostomy
8. Prior antineoplastic therapy for rectal cancer
9. Pregnant or breast feeding or of child bearing potential and unwilling to use effective contraceptive methods
10. On-treatment participation in an interventional clinical study 30 days prior to randomisation
11. Other concomitant antineoplastic therapy
12. Inability to comply with taking oral capecitabine/AN0025 medication
13. Active, uncontrolled infections
14. Active, disseminated coagulation disorder
15. Clinically significant cardiovascular disease = 6 months before randomisation
16. Prior invasive malignancy unless disease free >3 years (excluding basal cell carcinoma of the skin or carcinoma in situ)
17. Known allergic reactions to either oxaliplatin or AN0025 or both capecitabine and 5-FU
18. On medication with inhibitors of DPD
19. Psychosocial issues which may affect treatment compliance
20. Prolongation of corrected QT (QTc) interval to >480 msec when electrolyte balance is normal
21. Recent occurrence (within 3 months prior to randomisation) of a major thromboembolic event, such as pulmonary embolism or proximal deep vein thrombosis, unless stable on (>14 days) therapeutic anticoagulation (aspirin =325 mg daily or low-molecular-weight heparin (LMWH). Subjects with a history of clinically non-significant thromboembolic events, not requiring anticoagulation, are allowed on study
22. Subjects receiving oral warfarin are not eligible for this study (unless warfarin is discontinued at least 7 days prior to commencement of treatment and for the duration of the study, or oral warfarin is converted to LMWH, where local clinical opinion considers this an acceptable option)
23. Other systemic and local antitumor therapies such as chemotherapy, anti-tumour immunotherapy, radiotherapy or surgical interventions that may interfere / interact with the proposed treatment as part of the ARTEMIS trial
24. Other investigational drugs.

25. The following are prohibited during AN0025 therapy and therefore render patients ineligible for randomisation unless these can be switched to alternative medication prior to trial drug dosing:
25.1. Non-steroidal anti-inflammatory drugs (NSAIDs)
25.2. Aspirin at doses of higher than 325 mg daily
25.3. Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)
25.4. Uridine’5 diphospho-glucuronosyl transferase (UGT) inducers or inhibitors (atazanavir, probenecid, valproic acid, mefenamic acid, quinidine)
25.5. Anticoagulation with anti Xa agents (i.e.:Novel oral anticoagulants (NOACs): apixaban, rivaroxaban): Low Molecular Weight Heparin (LMWH) is the preferred form of initial anticoagulation. However, if, in the assessment of the investigator, changing to a NOAC is considered appropriate, then this is acceptable assuming the thrombotic event is medically controlled.
26. We recommend that patients DO NOT receive concomitant capecitabine and warfarin as the disturba

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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:<br>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 <br>2. No palpable tumour upon DRE, and <br>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). <br>(If the tumour is too proximal to reach with DRE then assessment will be via MRI and sigmoidoscopy alone).