DYNAMIC – Rectal

Patient selection for adjuvant chemotherapy after surgery, and chemotherapy drug choice remain major clinical dilemmas The aim of the DYNAMIC-Rectal study is to demonstrate that by incorporating ctDNA results in addition to the standard pathology risk assessment, the number of patients receiving adjuvant chemotherapy will be reduced.

Trial Status

In activation

Cancer Type

Rectal cancer

If you think this trial is relevant to your situation, please contact your Cancer Specialist to discuss further.

AIM

To make a decision about chemotherapy, a standard assessment of the pathologic risk of the tumour is made. The aim of the DYNAMIC-Rectal study is to demonstrate that by incorporating ctDNA results in addition to this standard risk assessment, the number of patients receiving adjuvant chemotherapy will be reduced.

SUMMARY

DYNAMIC-Rectal is a biomarker-driven study that aims to demonstrate that an adjuvant therapy strategy incorporating ctDNA results in addition to standard pathologic risk assessment will reduce the number of patients receiving adjuvant chemotherapy.

Patients with locally advanced rectal cancer who have completed chemo-radiation and surgery and are planned for chemotherapy are being invited to participate

Patients will be randomised 2:1 to be treated according to ctDNA results following surgery.  In the ctDNA informed group (Arm B), patients with a positive ctDNA result after surgery will receive 4 months of chemotherapy (fluoropyrimidine or combination fluoropyrimidine plus oxaliplatin).  Patients with a negative ctDNA result after surgery and pathological high risk disease will be treated at the doctor’s discretion whilst patients with intermediate or low risk disease will not be treated with adjuvant chemotherapy.  In the standard of care group (Arm A), patients will receive 4 months of adjuvant chemotherapy or no adjuvant therapy at the discretion of the treating doctor.

A total of 408 patients will be recruited over a 36-month accrual period.

Trial Status

In activation

Cancer Type

Rectal cancer

If you think this clinical trial may be relevant to your patient or to discuss further, please contact the Clinical Trial team.

Protocol Title

Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Locally Advanced Rectal Cancer:  A Multicentre Randomised Study (DYNAMIC-Rectal)

AIM

Primary Objective:

  • To demonstrate that an adjuvant therapy strategy incorporating ctDNA results in addition to standard pathologic risk assessment will reduce the number of patients receiving adjuvant chemotherapy

Secondary Objectives:

  • To demonstrate that an adjuvant therapy strategy incorporating ctDNA results in addition to standard pathologic risk assessment will not compromise recurrence-free survival compared to standard of care
  • To demonstrate that an adjuvant therapy strategy incorporating ctDNA results in addition to standard pathologic risk assessment will not compromise overall survival compared to standard of care
  • To correlate any change in serial ctDNA measurements during adjuvant chemotherapy with disease recurrence and overall survival

BACKGROUND

Despite guidelines recommending the routine use of adjuvant chemotherapy in locally advanced rectal cancer (LARC), there is little evidence in the modern era to support the routine use of post-operative chemotherapy in patients who received pre-operative chemo-radiation therapy. In fact, the results of EORTC 22921 combined with the results of other smaller studies argue against the routine use of chemotherapy for patients with clinical stage II or III disease who are undergoing pre-operative chemo-radiotherapy. Although the use of adjuvant FOLFOX appears promising in node-positive disease (ypN+), this comes with a toxicity price and the impact on overall survival yet to be proven. Clearly, better predictors of those patients who actually require adjuvant chemotherapy are needed (e.g. ctDNA-positivity indicating presence of minimal residual disease).

Our initial studies have demonstrated across multiple colorectal cancer cohorts, the potential utility of ctDNA as a marker of recurrence risk. The end goal for LARC patients is to integrate ctDNA analysis into routine clinical practice to guide clinical decision making, and most importantly to benefit patients. This initial study is powered to show that a ctDNA-based approach to adjuvant therapy will lead to substantially less patients receiving adjuvant therapy, which we believe is the only practical study design with a clinically significant endpoint, within the patient numbers that could be recruited. Importantly, this study will also demonstrate the feasibility of performing such as biomarker-driven study in the rectal cancer population.

CLINICAL TRIAL DESIGN

Patients with locally advanced rectal cancer treated with standard chemo-radiation will be randomised 2:1 to be treated according to ctDNA results following surgery.  In the ctDNA informed group (Arm B), patients with a positive post op ctDNA will receive 4 months of fluoropyrimidine or combination fluoropyrimidine plus oxaliplatin.  Patients with a negative post-op ctDNA and pathological high risk disease will be treated at the clinician’s discretion whilst patients with intermediate or low risk disease will not be treated with adjuvant chemotherapy.  In the standard of care group (Arm A), patients will receive 4 months of adjuvant chemotherapy or no adjuvant therapy at the discretion of the treating clinician.

Key Eligibility Criteria

Main Inclusion criteria:

  1. Patients aged ≥18 years of age
  2. Subjects with locally advanced rectal cancer (cT3-4N0 or cTanyN1-2 by MRI, or endorectal ultrasound if MRI is contraindicated) treated with curative intent
  3. Subjects treated with pre-operative long course fluoropyrimidine-based chemo-radiation and TME (total mesorectal excision) type surgery with negative (R0) resection margins.
  4. CT C/A/P prior to commencing pre-operative chemo-radiation demonstrating no metastatic disease
  5. An adequate paraffin embedded tumour sample (from pretreatment biopsy or resection specimen, with a preference for the former) is available for molecular testing within 35 days after surgery
  6. Fit for adjuvant chemotherapy
  7. ECOG performance status 0-2

Main Exclusion criteria:

  1. History of another primary cancer within the last 3 years, with the exception of non-melanomatous skin cancer and carcinoma in situ.
  2. Patients with multiple primary colorectal cancers
  3. Inadequate organ function:
    1. Moderate/severe renal impairment (GFR<30 ml/min), as calculated by the Cockcroft and Gault equation
    2. Absolute neutrophil count <1.0×109/L
    3. Platelet count <75×109/L
    4. Haemoglobin <80 g/L
    5. Aspartate aminotransferase/Alanine aminotransferase >2.5 x upper limit of normal
  4. Evidence of active infection
  5. Clinically significant cardiovascular disease

Medical or psychiatric condition or occupational responsibilities that may preclude compliance with the protocol

Contact Email

DYNAMIC-RECTAL@mh.org.au

Principal Investigator

A/Professor Jeanne Tie

Detailed Information Available on

MORE DETAILED INFORMATION: Available online at the Australian New Zealand Clinical Trial Registry (ANZCTR) here

FUNDING

NHMRC project grant