Table 3.
Selected clinical trials investigating the ctDNA-guided treatment strategies in patients with colorectal cancer *.
| Study Identifier | Study Phase | Study Population | n | ctDNA Assay | Study Description | Primary Endpoint |
|---|---|---|---|---|---|---|
|
NCT04068103 (COBRA) |
II/III | Stage II CC without high-risk features | 1408 | LUNAR-1 (Guardant Health) |
Arm A: active surveillance. Arm B: ctDNA directed therapy (ctDNA-positive → FOLFOX/CAPOX for 6 months, ctDNA-negative → active surveillance) | Clearance of ctDNA with ACT (phase II) and RFS (phase III) |
|
NCT05174169 (CIRCULATE-US) |
II/III | Stage II and III CC | 1912 | Signatera | Cohort A: Arm 1—ctDNA-negative treated with FOLFOX 3–6 months/CAPOX 3 months. Arm 2—ctDNA-negative undergoing serial ctDNA monitoring and no treatment. Cohort B: Arm 3—ctDNA-+ve treated with FOLFOX/CAPOX for 6 months. Arm 4—ctDNA-+ve treated with mFOLFIRINOX |
TTPos (time from randomization until ctDNA-positive event), DFS |
|
NCT04120701 (CIRCULATE-PRODIGE 70) |
III | Resected Stage II CC | 1980 | ddPCR | ctDNA-positive → randomized (2:1) to receive ACT or no ACT. ctDNA-negative → surveillance. | 3-year DFS in ctDNA-positive patients. |
| ACTRN12615000381583 (DYNAMIC-II) |
III | Stage II CC | 450 | Safe-SeqS | Arm A: positive for ctDNA → ACT, negative for ctDNA → surveillance. Arm B: treated at the discretion of the clinicians. | RFS |
| ACTRN12617001566325 (DYNAMIC-III) | II/III | Stage III CC | 1000 | Safe-SeqS | Arm A: standard of care. Arm B: ctDNA-informed (ctDNA-negative → therapy de-escalation; ctDNA-positive → therapy escalation) | RFS |
| GALAXY (UMIN000039205) |
Prospective observational | Stages II∓IV CRC | 2500 | Signatera | Serial ctDNA monitoring after surgery. If ctDNA-negative--> VEGA trial (therapy de-escalation). If ctDNA-+ve → ALTAIR trial. | DFS |
| VEGA (jRCT1031200006) |
III | High-risk stage II or low-risk stage III CC | 1240 | Signatera | Designed to compare adjuvant CAPOX for 3 months vs. observation for GALAXY patients with negative ctDNA at week 4 after surgery. | DFS |
|
NCT04089631 (CIRCULATE AIO-KRK-0217) |
III | Stage II CC | 4812 | NGS | Patients positive for ctDNA post-resection are randomized to observation vs. capecitabine or CAPOX (investigator’s choice) × 6 months | DFS |
| MEDOCC-CrEATE (NL6281/NTR6455) |
III | Stage II CC | 1320 | PGDx elio™ | Standard of care surveillance vs. ctDNA-guided ACT (ctDNA-positive: 6 months of CAPOX; ctDNA-negative: surveillance) | The proportion of patients receiving ACT after surgery if ctDNA-positive. |
|
NCT03748680 (IMPROVE-IT) |
II | Stage I and II CRC | 64 | ddPCR, NGS | ctDNA-positive patients randomized to observation vs.FOLFOX or CAPOX for 6 months. | DFS |
|
NCT04264702 (BESPOKE) |
Prospective Observational |
Stage II and III CRC | 1000 | Signatera | Serial ctDNA testing following surgery and ACT vs. observation at the discretion of the treating clinician. Control arm-matched stage II and III patients with a minimum 2 years of follow-up data. | 1. Impact of ctDNA on adjuvant treatment decisions. 2. Rate of ctDNA detected recurrence while asymptomatic. |
|
NCT04259944 (PEGASUS) |
II | Resected MSS stage III and high-risk stage II (T4N0) CC | 140 | LUNAR-1 (Guardant Health) |
ctDNA-guided ACT. (i) ctDNA-positive → CAPOX for 3 months; (ii) ctDNA-negative → capecitabine for 6 months but will be retested after 1 cycle, and if found ctDNA-positive, will be switched to CAPOX. | The number of patients negative for ctDNA post-op and post ACT later turning ctDNA-positive or developing radiographic relapse. |
|
NCT04084249 (IMPROVE-IT2) |
III | Stage III or high-risk stage II CRC |
254 | ddPCR, NGS | Patients were randomized to ctDNA-guided post-operative surveillance or standard-of-care CT-scan surveillance. | Fraction of patients with relapse receiving curative resection or local treatment |
|
NCT03803553 (ACT-3) |
III | Stage III CC | 500 | LUNAR-1 (Guardant Health) |
ctDNA-enriched second-line adjuvant therapy: patients are distributed post-ACT as follows- 1. ctDNA-negative: active surveillance; 2. ctDNA-positive: (a) MSS patients- 6 months of FOLFIRI vs. active surveillance, (b) MSI high-6 months of nivolumab, (c) BRAF mutant and MSS-6 months of BRAF directed therapy. |
DFS, ctDNA clearance rate |
|
NCT04457297 (ALTAIR) |
III | Stage II∓IV CRC | 240 | Signatera | TAS-102 for 6 months vs. placebo for patients positive for ctDNA following completion of standard ACT and no evidence of relapse radiologically in the GALAXY study | DFS |
| NCT03436563 | Ib/II | Stage IV CRC | 74 | Signatera | Patients with metastatic CRC positive for ctDNA following resection of all metastases will receive M7824 (anti-PDL1/TGFbetaRII fusion protein) for 6 doses | ctDNA clearance rate |
| NCT04589468 | Ia/b | CRC, breast, and prostate cancer stage I–III | 70 | Signatera | Patients with primary breast, prostate, or colorectal cancer and detectable ctDNA (n = 50) post definitive treatment will perform one of five escalating dose levels of exercise. | RP2D of exercise |
|
NCT04853017 (Amplify-201) |
I/II | Solid tumors, including CRC with RAS mutation | 18 | Signatera | Patients with tumors harboring RAS mutation and minimal residual disease with detection of ctDNA receive different dose levels of ELI-002, a RAS targeting vaccine. |
1. MTD of ELI-002 and the RP2D 2. Safety |
Abbreviations: ctDNA, circulating tumor DNA; CC, colon cancer; ACT, adjuvant chemotherapy; mFOLFOX6, 5-Fluorouracil, leucovorin, and oxaliplatin; ddPCR, droplet digital polymerase chain reaction; NGS, next-generation sequencing; RFS, relapse-free survival; CAPOX, capecitabine and oxaliplatin; DFS, disease-free survival; MSS, microsatellite stable; Safe-SeqS, safe sequencing system; CRC, colorectal cancer; MTD, maximum tolerated dose; RP2D, recommended phase 2 dose. * Clinicaltrials.gov accessed between 20 April 2022 and 20 May 2022.