CO.29

Primary Objective:
 To evaluate the impact of de-escalation/escalation treatment strategies as informed by post-op ctDNA-informed management:
o In ctDNA negative patients the trial will evaluate whether a de-escalation treatment strategy is non-inferior to standard of care treatment with respect to the 3-year recurrence-free survival rate.
o In ctDNA positive patients the trial will evaluate whether an escalation treatment strategy is superior to standard of care treatment as measured by the 24 month recurrence-free survival.

Secondary Objectives:
 To demonstrate that a ctDNA-informed adjuvant therapy approach will not compromise recurrence free survival compared to standard of care adjuvant therapy in patients with NEGATIVE post-op ctDNA
 To demonstrate an acceptable rate of de-escalation in the ctDNA-informed negative cohort  To examine the proportion of patients in whom escalated chemotherapy has reversed the ctDNA status from positive to negative post completion of the escalated treatment regime in the ctDNA-informed positive cohort  To compare the 3-year recurrence free survival rates between ctDNA-informed adjuvant
therapy (i.e. treatment escalation) and standard of care adjuvant therapy approach in patients with POSITIVE post-op ctDNA
 To compare the overall survival between ctDNA-informed adjuvant therapy and standard of care adjuvant therapy approach in patients with NEGATIVE post-op ctDNA  To compare the overall survival between ctDNA-informed adjuvant therapy and standard of care adjuvant therapy approach in patients with POSITIVE post-op ctDNA
 To correlate end of treatment ctDNA results with recurrence-free and overall survival

Exploratory Objectives:
 To compare the ctDNA positivity rate at the completion of adjuvant treatment in the ctDNA informed negative (de-escalated) and positive (escalated) cohort
 To demonstrate the feasibility of an adjuvant chemotherapy strategy (treatment de-escalation or escalation) based on post-operative ctDNA results.
 To explore the health economic impact of a ctDNA-informed adjuvant therapy approach compared to standard of care adjuvant therapy The major driver of this study is to demonstrate that a ctDNA-directed approach to adjuvant chemotherapy for patients with stage III colon cancer could lead to significant gains in preventing recurrence through treatment escalation, ultimately improving survival.
However, also of great importance is the potential of a ctDNA-directed approach to reduce the unnecessary use of treatment (treatment de-escalation) in low risk patients (reducing treatment related toxicity, reducing direct treatment related cost, and reducing indirect treatment related costs, such as time off work). This design incorporates two separate clinical objectives; (i) non-inferiority and (ii) benefit.
This is a prospective multi-centre, phase II/III randomised controlled study enrolling 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).