Table 2.
Ongoing ctDNA-based randomised adjuvant trials in non-metastatic colorectal cancer.
| Trial Name/Country | Patient Population | Sample Size | ctDNA Assay | Timing of ctDNA Testing | Trial Intervention | Primary Objective |
|---|---|---|---|---|---|---|
| ctDNA-Guided Strategy Design | ||||||
| DYNAMIC (ACTRN-12615000381583) Australia |
Stage II colon cancer | 450 | Safe-SeqS | Week 4 and 7 post-op |
Standard of care: clinician determined management (surveillance or adjuvant chemotherapy) based on standard clinicopathological features ctDNA-guided: ctDNA-positive → adjuvant chemotherapy; ctDNA-negative → surveillance |
To demonstrate that an adjuvant therapy strategy based on post-op ctDNA results will reduce the number of patients receiving adjuvant chemotherapy without compromising recurrence-free survival |
| DYNAMIC-III (ACTRN-12617001566325) Australia/New Zealand |
Stage III colon cancer | 1000 | Safe-SeqS | Week 5–6 post-op |
Standard of care: clinician determined standard of care adjuvant chemotherapy based on clinical risk ctDNA-guided: ctDNA-positive → escalated chemotherapy regimen from pre-planned treatment (increase duration or number of agents); ctDNA-negative → de-escalated chemotherapy regimen from pre-planned treatment (reduction in duration or number of agents) |
To evaluate the impact of de-escalation/escalation treatment strategies as informed by post-op ctDNA-informed management
|
| DYNAMIC-RECTAL (ACTRN-12617001560381) Australia/New Zealand |
Locally advanced rectal cancer | 408 | Safe-SeqS | Week 4 and 7 post-op |
Standard of care: clinician determined management (surveillance or adjuvant chemotherapy) based on standard clinicopathological features ctDNA-guided: ctDNA-positive → adjuvant chemotherapy; ctDNA-negative and ypN0 → surveillance; ctDNA-negative and ypN+ → surveillance or adjuvant chemotherapy at clinician’s choice |
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 without compromising recurrence-free survival |
| TRACC (NCT04050345) [79] United Kingdom |
High risk stage II, stage III colorectal cancer | 1621 | NGS-based 22-gene colorectal panel | <8 weeks post-op, 3 months post-op |
Standard of care: 6 months of capecitabine or 3 months of CAPOX ctDNA-guided: ctDNA-positive → standard adjuvant chemotherapy; ctDNA-negative → de-escalate treatment but re-escalate if ctDNA becomes positive at 3 months |
|
| MEDOCC-CrEATE (NL6281/NTR6455) [80] Netherlands |
Stage II colon cancer | 1320 | PGDx elio™ | 4–21 days post-op |
Standard of care: surveillance ctDNA-guided: ctDNA-positive → 6 months of CAPOX; ctDNA-negative → surveillance |
To investigate the willingness of patients to receive adjuvant chemotherapy after detection of ctDNA post-surgery |
| Marker-by-Treatment Interaction Design | ||||||
| NRG GI-005 (COBRA) NCT04068103 [81] United States/Canada |
Stage IIA colon cancer | 1408 | Guardant LUNAR-1™ | Post-op |
Standard of care: Surveillance ctDNA-guided: ctDNA-positive → adjuvant FOLFOX/CAPOX; ctDNA-negative → surveillance |
|
| CIRCULATE AIO-KRK-0217 (NCT04089631) [82] Germany |
Stage II colon cancer (MSS tumours) | 4812 | Not reported | Post-op | ctDNA-positive patients randomised to: Standard of care: surveillance Experimental: adjuvant chemotherapy (capecitabine or CAPOX) |
To compare the disease-free survival in patients who are positive for postoperative ctDNA treated with or without adjuvant chemotherapy |
| CIRCULATE PRODIGE 70 (NCT04120701) [83] France |
Stage II colon cancer | 1980 | ddPCR (2 methylated markers WIF1 and NPY) | Week 2–8 post-op | 198 ctDNA-positive patients randomised to: Standard of care: surveillance Experimental: adjuvant FOLFOX |
To demonstrate a 17.5% gain in 3-year DFS in post-op ctDNA-positive patients treated with adjuvant FOLFOX compared to observation alone |
| VEGA (UMIN000039205) [84] Japan |
High-risk stage II, low-risk stage III colon cancer—ctDNA-negative | 1240 | Signatera™ | 1-month post-op | Post-op ctDNA-negative patients randomised to: Standard of care: 3 months of CAPOX Experimental: Surveillance
|
To demonstrate the non-inferiority of observation vs. adjuvant CAPOX with absence of ctDNA at 1 month post-surgery |
| ctDNA-Enriched 2nd Line Adjuvant Therapy Trial | ||||||
| ALTAIR (UMIN000039205) [85] Japan |
Stage II/III colorectal cancer or stage IV with resectable metastases | 240 | Signatera™ | 1-month post-op and after 3 months of standard adjuvant CAPOX | Patients who are ctDNA-positive after completion of 3 months adjuvant CAPOX are randomised to: Standard of care: placebo/surveillance Experimental: trifluridine/tipiracil |
To demonstrate the superiority of trifluridine/tipiracil over placebo in patients with ctDNA that remains positive after standard adjuvant therapy |
| ACT-3 (NCT04259944) United States |
Stage III colorectal cancer | 500 | Guardant LUNAR-1™ | 3–6 weeks post adjuvant chemo | Patients who are ctDNA-positive after completion of 3–6 months of adjuvant FOLFOX/CAPOX are randomised to: Standard of care: surveillance Experimental:
|
To demonstrate the superiority of FOLFIRI over surveillance in patients with positive ctDNA after standard adjuvant therapy |
| ctDNA-Guided Surveillance Strategy Design | ||||||
| IMPROVE-IT2 (NCT04084249) [86] Denmark |
High risk stage II, stage III colorectal cancer | 254 | Droplet digital PCR (colorectal panel) | Every 4 months post-op for 24 months |
Standard of care: standard Danish follow-up program (CT scans at 12 and 36 months) ctDNA-guided surveillance: 3-monthly FDG-PET/CT for patient with positive ctDNA during surveillance |
To demonstrate that ctDNA guided post-operative surveillance combining ctDNA and radiological assessments could result in earlier detection of recurrent disease and identify more patients eligible for curative treatment |