Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Stage III Colon Cancer: A Multicentre Phase II/III Randomised Controlled Study (DYNAMIC-III)

This design incorporates two separate clinical objectives; (i) non-inferiority and (ii) benefit. This prospective multi-centre, phase II/III randomised study aims to enrol a total of 1000 stage III colon cancer patients. Patients will be randomised 1:1 to be treated according to post-op ctDNA results (Arm B: ctDNA-informed), or per standard of care (Arm A: SOC). Enrolment will be stratified by participating centre and clinical risk groups (low risk = T1-3N1; high risk = T4 and/or N2). Patients should be screened up to 6 weeks after surgery and tumour samples will be made available in 5 working days from consent for mutation analysis. Patients will have a blood draw during week 5-6 post-op for ctDNA analysis (ctDNA-1: post-op day 32 to day 42). Clinicians are to nominate their standard of care adjuvant chemotherapy regimen (no chemotherapy, single agent fluoropyrimidine or combination fluropyrimidine plus oxaliplatin) at the time of enrolment prior to randomisation. Randomisation will occur after the post-op ctDNA blood draw and receipt of sufficient tumour tissue. Additional blood collection time-points will depend on the schedule of adjuvant chemotherapy. Formalin-fixed paraffin embedded tumour tissue and the study bloods sample will undergo ctDNA analysis at Johns Hopkins University. In the ctDNA-informed arm (Arm B), the post-op ctDNA result will be made available to the treating clinician approx 4-5 weeks after receipt of tumour tissue. Adjuvant chemotherapy will commence after the ctDNA result becomes available or, where the treating clinician wishes to commence adjuvant treatment before the result is available, an individual patient may commence on standard of care treatment no earlier than 6 weeks post-op, and then switch to the ctDNA informed strategy as per the protocol. Patients who are "ctDNA negative" will be managed with a de-escalation adjuvant treatment strategy and those who are "ctDNA-positive" will be managed with an escalation adjuvant treatment strategy. In the standard of care arm, patients and their clinicians will be blinded to the ctDNA results and will receive adjuvant chemotherapy as per standard of care. Patients in Arm B receiving 3 or 6 months of adjuvant chemotherapy will have blood collection for ctDNA analysis prior to and during treatment (ctDNA-2, ctDNA-2A +/- ctDNA-2B) and at the end of treatment (ctDNA-3). These results will not be routinely made available to the patients or clinicians. For patients where standard treatment of oxaliplatin based treatment is escalated to FOLFOXIRI, this will be given for at least 6 cycles. TREATMENT REGIMENS: Unless otherwise specified, duration of chemotherapy (3 or 6 months) and dose modifications on treatment are at clinician's discretion. Recommended single agent fluoropyrimidine based chemotherapy regimens include: 1. 2 weekly De Gramont (modified) a) Leucovorin 50mg IV (intravenous) b) Fluorouracil 400mg/m2 IV (intravenous) c) Fluorouracil 2400mg/m2 CIV (continuous intravenous) pump over 46 hours 2. Weekly modified QUASAR a) Leucovorin 50mg IV (intravenous) b) Fluorouracil 375-450mg/m2 IV (intravenous)(dose as per institutional standard of care) 3. Weekly modified Roswell Park (weekly for 6 weeks followed by 2 week break) a) Leucovorin 50mg IV (intravenous) b) Fluorouracil 500mg/m2 IV (intravenous) 4. Capecitabine orally days 1 to 14, every 21 days (dose as per institutional standard of care) Recommended combination oxaliplatin-based chemotherapy regimens include 12 or 24 weeks of: 1. 2 weekly FOLFOX6 (modified) a) Oxaliplatin 85mg/m2 IV (intravenous) b) Leucovorin 50mg IV (intravenous) c) Fluorouracil 400mg/m2 IV (intravenous) d) Fluorouracil 2400mg/m2 CIV (continuous intravenous) pump over 46 hours 2. 3 weekly CAPOX a) Oxaliplatin 130mg/m2 b) Capecitabine 1000mg/m2 twice a day orally days 1 to 14, every 21 days Recommended triplet chemotherapy regimen includes 12 to 24 weeks of: 1. 2 weekly FOLFOXIRI a) Irinotecan 165mg/m2 IV (intravenous) b) Oxaliplatin 85 mg/m2IV (intravenous) c) Leucovorin 50mg IV (intravenous) d) Fluorouracil 3200mg/m2 CIV (continuous intravenous) pump over 46 hours Standard of Care Arm (Arm A) Clinician's choice of: - no adjuvant chemotherapy - fluoropyrimidine chemotherapy -combination fluoropyrimidine plus oxaliplatin chemotherapy ctDNA-Informed Arm (Arm B) De-escalation or escalation chemotherapy regimen will be based on clinician's chosen standard of care chemotherapy regimen prior to randomisation Standard of care choice - no chemo -ctDNA Negative: No adjuvant chemotherapy -ctDNA Positive: 3 months of fluoropyrimidine alone Standard of care choice - 6 months of fluoropyrimidine alone chemotherapy -ctDNA Negative: No adjuvant chemotherapy or 3 months of fluoropyrimidine chemotherapy -ctDNA Positive: 6 months of combination fluoropyrimidine plus oxaliplatin chemotherapy Standard of care choice - 3 months of combination fluoropyrimidine plus oxaliplatin chemotherapy -ctDNA Negative: fluoropyrimidine chemotherapy -ctDNA Positive: 6 months of combination fluoropyrimidine plus oxaliplatin or triplet chemotherapy (FOLFOXIRI) for 6 cycles, followed by further treatment at clinician discretion. Standard of care choice - 6 months of combination fluoropyrimidine plus oxaliplatin chemotherapy -ctDNA Negative: fluoropyrimidine alone or 3 months of combination fluoropyrimidine plus oxaliplatin -ctDNA Positive: triplet chemotherapy (FOLFOXIRI) for 6 cycles, followed by further treatment at clinician discretion. Details of adjuvant chemotherapy received, including start and stop dates, dose received, dose reduction, reason for dose reduction/interruption and reason for stopping treatment will be recorded. Interim Analysis for Futility: Prior to completing the phase II component, futility of the observed de-escalation rate will be evaluated. After 38 patients in the ctDNA negative cohort have been enrolled and managed according to the ctDNA result, if fewer than 26 of these patients have been de-escalated then consideration will be given to either modifying the protocol or not continuing to the 100 patients in this group.