ARTEMIS

• Patients age ≥18 years old;

• Eastern Cooperative Oncology Group (ECOG) PS 0 or 1;

• Capable of informed consent;

• Able to fully understand trial treatment enough to provide informed consent;

• Biopsy-proven rectal adenocarcinoma;

• Staged on high-resolution MRI as:

o T3b-4a OR

o TanyN1-2 OR

o TanyEMVI+ OR

o 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) OR

o low tumours with involvement of the anal intersphincteric plane or with levator involvement.

Within 14 days pre-randomisation the following must be met:

• Estimated creatinine clearance ≥50 mls/min (using a validated creatinine clearance calculation e.g.,Cockcroft-Gault or Wright formula);

• Haemoglobin ≥9.0g/dL;

• Neutrophils >1.5 x 109/L;

• Platelets >100 x 109/L;

• Adequate blood coagulation function as evidenced by a prothrombin time (PT) <1.5 x normal;

• Alkaline phosphatase (ALP) ≤2.5 × upper limit of normal (ULN); serum transaminase (either alanine aminotransferase (ALT) or aspartate aminotransferase (AST)) ≤2.5 × ULN; total bilirubin ≤1.5 × ULN except for unconjugated hyperbilirubinemia or Gilbert’s syndrome. 

Unequivocal distant metastatic disease;

• Previous pelvic radiotherapy;

• MRI defined predominantly mucinous tumour i.e. more than one third of tumour volume assessed to consist of mucin;

• Biopsy-proven neuroendocrine tumour;

• Definite MRI pelvic side wall lymph node involvement,invasion of adjacent organ,ischio-rectal fossa involvement;

• 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));

• Defunctioning colostomy or ileostomy;

• Prior antineoplastic therapy for rectal cancer;

• Pregnant or breast feeding; or of child bearing potential and unwilling to use effective contraceptive methods;

• On-treatment participation in an interventional clinical study 30 days prior to randomisation;

• Other concomitant antineoplastic therapy;

• Inability to comply with taking oral capecitabine/AN0025 medication;

• Active,uncontrolled infections;

• Active,disseminated coagulation disorder;

• Clinically significant cardiovascular disease ≤ 6 months before randomisation;

Prior invasive malignancy unless disease free >3 years (excluding basal cell carcinoma of the skin or carcinoma in situ);

• Known allergic reactions to either oxaliplatin or AN0025 or both capecitabine and 5-FU;

• On medication with inhibitors of dihydropyrimidine dehydrogenase (DPD);

• Psychosocial issues which may affect treatment compliance;

• Prolongation of corrected QT (QTc) interval to >480 msec when electrolyte balance is normal;

• 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;

• 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);

• Presently receiving 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;

• Presently receiving other investigational drugs.

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:

• Non-steroidal anti-inflammatory drugs (NSAIDs);

• Aspirin at doses of higher than 325 mg daily;

• Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs);

• Uridine’5 diphospho-glucuronosyl transferase (UGT) inducers or inhibitors (atazanavir,probenecid,valproic acid,mefenamic acid,quinidine);

• Anticoagulation with anti Xa agents (ie: 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.

We recommend that patients DO NOT receive concomitant capecitabine and warfarin as the disturbance in warfarin metabolism during capecitabine treatment is unpredictable and difficult to manage. Wherever possible we would recommend either treating the patient with low molecular weight heparin instead of warfarin,or changing the patient to FOLFOX treatment rather than CAPOX. If the Local Investigator feels there is no alternative to giving capecitabine and warfarin concurrently then these patients MUST have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. 

Lead Research Nurse: Rashmi Madan (x2136) Rashmi.Madan@LTHTR.nhs.uk

Clinical Trials Administrator : Yecora Lecanda-Swarbrick (x3766)