Locally advanced rectal cancer Cancer
Conditions
Interventions
Radiotherapy: All patients will receive standard radiotherapy delivered using intensity-modulated radiotherapy (IMRT), Volumetric-modulated arc therapy (VMAT) or TomoTherapy to treat an elective pelvi
Sponsors
University of Leeds
Eligibility
Sex/Gender
All
Age
18 Years to 100 Years
Inclusion criteria
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 (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
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 t | — |
Countries
England, Northern Ireland, Scotland, United Kingdom, Wales
Outcome results
None listed