DYNAMIC-III

Protocol Title

DYNAMIC-III:  Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Stage III Colon Cancer:  A Multi-centre Phase II/III Randomised Controlled Study (Protocol No: ctDNA-08)

AIM

Primary Objective:

• To demonstrate that a de-escalation/escalation treatment strategy using ctDNA-informed management is non-inferior to standard of care treatment for stage III colon cancer as measured by the rate of 3-year 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 a ctDNA-informed adjuvant therapy and the standard of care adjuvant therapy approach in patients with POSITIVE post-op ctDNA
• To correlate the 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

BACKGROUND

In the adjuvant setting, post-operative circulating tumour DNA (ctDNA) has been shown to be a marker of minimal residual disease, with the presence of ctDNA predicting recurrence in separate series of stage II colon cancers and locally advanced rectal cancers.

For patients with stage III colon cancer adjuvant chemotherapy improves overall survival but some individual patient will receive adjuvant therapy and still recur, whereas others will not recur in the absence of any adjuvant treatment.  For every patient with stage III colon cancer, a reliable biomarker could improve their adjuvant management decision (treatment regimen and/or treatment duration), allowing therapy to be tailored to each patient’s risk of recurrence and moving away from a generic “one size fits all” approach. Specifically, for the great majority of patients, a biomarker that defines a given patient to be either at very high risk (such as a positive ctDNA test) or at very low risk (such as a negative ctDNA test) of recurrence would allow treatment to be escalated in very high risk cases (enhancing the likelihood of preventing disease recurrence and death) or de-escalated for patients with a very low risk of recurrence (reducing treatment related toxicity, reducing direct treatment related cost, and reducing indirect treatment related costs, such as time off work, with minimal to no risk of compromising survival outcome).

CLINICAL TRIAL DESIGN

This is a prospective, multi-centre, phase II/III randomised study enrolling a total of 1000 stage III colon cancer patients. Patients will be randomised 1:1 to be treated according to ctDNA results (Arm B: ctDNA-informed), or per standard of care (Arm A: SOC). Enrolment will be stratified by treating centre and clinical risk groups (low risk = T1-3N1; high risk = T4 and/or N2).

Patients should be screened within 21 days after surgery and tumour samples be made available in 3 working days from consent for mutation analysis. Patients will have a blood draw during week 5-6 post-op (ctDNA-1: post-op day 32-42) for ctDNA analysis.  Clinicians are to nominate their standard of care adjuvant chemotherapy regimen (no chemotherapy, single agent fluoropyrimidine or combination fluoropyrimidine plus oxaliplatin) at the time of enrolment and prior to randomisation. Randomisation will occur after the post-op ctDNA blood draw. Additional blood collection time-points will depend on the randomisation and the schedule of adjuvant chemotherapy (see sampling schedule below). Formalin-fixed paraffin embedded tumour and matched normal tissue, and the study blood sample will be shipped to the Ludwig Center at Johns Hopkins (Vogelstein laboratory) for ctDNA analysis.

In the ctDNA-informed arm (Arm B), the post-op ctDNA result will be made available to the treating clinician within 8 weeks post-op. 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 whilst those who are “ctDNA-positive” will be managed with an escalation adjuvant treatment strategy (see treatment regimens below). In the SOC arm (Arm A), patients/clinicians will be blinded to their 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 during adjuvant chemotherapy (ctDNA-2A +/- ctDNA-2B) (see sampling schedule below). All patients receiving adjuvant chemotherapy will have blood collection for ctDNA analysis at the end of treatment (6 +/- 2 weeks post day 1 of the final cycle of chemo – ctDNA-3). These results will not be routinely made available to the patients or treating clinicians.

For patients where treatment is escalated to FOLFOXIRI, this will be given for at least 6 cycles. Treatment beyond 6 cycles will be at clinician’s discretion. Patients who experience unacceptable toxicity during treatment with FOLFOXIRI should either undergo a dose reduction or de-escalate to FOLFOX alone at clinician discretion.

All patients will be followed up every 3 months for 2 years, then every 6 months for 3 years.

Data including patient demographics, pathology details, treatment details, treatment-related hospitalisation, surveillance CEA results, surveillance CT reports, date of recurrence, and details of recurrence, date of death and cause of death will be recorded.

As all treatments are given and managed in line with standard clinical care, safety parameters will not be collected, except for treatment-related hospitalisation and SUSAR for the small number of patients treated with FOLFOXIRI.

Patients Recruited

Click here to access the table and view recruitment data on all AGITG open trials:

Open Trial Recruitment Table

Contact Email

Principal Investigators

A/Professor Jeanne Tie and Professor Peter Gibbs

Detailed Information Available on

More detailed information available online at the Australian New Zealand Clinical Trial Registry (ANZCTR) here

FUNDING

The Marcus Foundation