This month we feature clinical trials for colorectal cancer patients with minimal residual disease (MRD) after curative-intent treatment. MRD describes microscopic residual disease, where a very small number of cancer cells may remain in the body during or after treatment. MRD cannot be seen using traditional scans and imaging (such as a CT scan, PET scan, or MRI). Instead, detecting MRD requires highly sensitive laboratory methods. The presence of circulating tumor DNA (ctDNA), or small pieces of DNA released by tumor cells into the bloodstream, in a blood sample can be used to identify MRD.

NCT05174169

CIRCULATE-North America (open in the United States and Canada) is an actively enrolling (714/1912 slots filled), multi-center phase II/III trial for non-metastatic colon cancer patients.

Who is eligible? Patients must have stage IIB/C or stage III microsatellite stable (MSS) colon cancer with successful surgical removal of the primary tumor with clear margins.

What is the goal of this study? This trial aims to determine whether ctDNA status after surgery can be used to make decisions about adjuvant chemotherapy in stage II/III colon cancer patients.

For example, non-metastatic colon cancer patients with no detectable ctDNA (ctDNA negative) after curative-intent surgery are at a lower risk for recurrence and may not need adjuvant chemotherapy, while patients with detectable ctDNA (ctDNA positive) are at a higher risk for recurrence and may need more aggressive adjuvant therapy. This trial tests these ideas and will compare outcomes between different arms in the trial.

What can patients expect? Patients are given a Signatera^TM test, a tumor-informed (personalized) blood test, to determine their ctDNA status (positive or negative) after surgery.

Patients who are ctDNA negative (cohort A) are randomized to one of the following arms:

• Six to twelve cycles of FOLFOX or four cycles of CAPOX (standard of care)
• Serial ctDNA monitoring without adjuvant chemotherapy (experimental)

Patients who are in cohort A (ctDNA negative) that have a positive ctDNA test at any point are allowed to cross over to cohort B (ctDNA positive).

Patients who are ctDNA positive (cohort B) are randomized to one of the following arms:

• Twelve cycles of FOLFOX or eight cycles of CAPOX (standard of care)
• Twelve cycles of FOLFIRINOX (experimental)

What is being measured? The primary endpoints are time to positive ctDNA test (TTpos) and disease-free survival.

This trial is expected to complete enrolling and result out after follow up in the next few years. This trial will establish the “clinical utility”- whether ctDNA status can be used to safely escalate or de-escalate adjuvant chemotherapy. This way only those patients that benefit from adjuvant chemotherapy will need to have it, thereby sparing everyone else from chemotherapy side effects. Those who are ctDNA positive and may need stronger chemotherapy would be able to get that as well.

NCT03803553

The Stand Up To Cancer ACT3 trial is an actively enrolling, multicenter, phase III clinical trial for stage III colon cancer patients. The trial is now open at Massachusetts General Hospital, Memorial Sloan Kettering Cancer Center, and Cornell.

Who is eligible? Stage III colon cancer patients who have completed surgery and adjuvant chemotherapy.

What is the goal of this study? After surgery and adjuvant chemotherapy, it is standard of care for patients to begin active surveillance. This study asks whether additional treatment (FOLFIRI or a biomarker-directed treatment) can reduce recurrence (versus active surveillance) in patients who are ctDNA positive after surgery and initial adjuvant chemotherapy.

What can patients expect? Participants are given a Guardant Reveal blood (ctDNA MRD) test to determine their ctDNA status (positive or negative).

Patients who are ctDNA negative will receive active surveillance, which includes observation and monitoring with imaging, tumor markers, and serial ctDNA monitoring. If ctDNA positive within the first year, they are randomized to one of the treatment arms as described below.

Patients who are ctDNA positive and have one of the tumor biomarkers will be assigned to the following treatment arms:

• HER2 overexpression/amplification: Trastuzumab + Pertuzumab (up to eight cycles)
• BRAF V600E: Encorafenib/Binimetinib/Cetuximab (up to twelve cycles)
• MSI-H/dMMR: Nivolumab (up to twelve cycles)

All other patients who are ctDNA positive are randomized to one of the following arms:

• Active surveillance (standard of care)
• FOLFIRI (up to twelve cycles)

What is being measured? The primary endpoints in this study are disease-free survival and clearance rate of ctDNA between ctDNA positive patients on active surveillance and those treated with FOLFIRI.

This is another trial whose results will inform the field about the clinical utility of ctDNA testing as well as what treatments may be beneficial for patients who are ctDNA positive after completing adjuvant treatment.

This is a small (15 participants), actively enrolling phase II trial. This trial is only open at MD Anderson Cancer Center in Houston, Texas.

Who is eligible? Patients with any stage colon or rectal cancer that have completed curative intent treatments, including adjuvant therapy, and are ctDNA positive with no clinically detectable disease.

What is the goal of this study? This study investigates the safety and efficacy of AMB-05X in CRC patients with MRD (defined by a positive ctDNA test and no clinically detectable disease).

What can patients expect? This is a single-arm trial, meaning that all participants receive the same treatment. All participants will receive AMB-05X (an anti-CSF1R monoclonal antibody) which is given intravenously.

What is being measured? The primary outcome measure is safety and adverse events.

The anti-CSF1R monoclonal antibody AMB-05X enhances T-cell infiltration and antitumor T-cell immune responses, potentially eliminating undetectable cancer cells in CRC patients who appear cancer-free. This might lower the odds of the cancer coming back, giving patients a better chance at staying healthy over the long term.

(with a new cohort for stage IV patients with liver metastases that are NED after surgery)
NCT04486378

This is a phase II actively recruiting clinical trial for patients who have had surgery for high-risk stage II or stage III colorectal cancer. This is a multi-center trial with 118 locations across the United States and Europe.

Who is eligible? Stage II or III microsatellite stable (MSS) rectal or colon cancer patients with a positive ctDNA test after total tumor resection and that have completed at least three months of adjuvant chemotherapy. Additionally, there is a biomarker cohort for patients irrespective of post-surgical ctDNA status (positive or negative).

As of November 2024, this study also enrolls stage IV CRC patients with a positive ctDNA test after primary tumor resection and curative intent hepatectomy to treat liver metastases and have completed adjuvant chemotherapy.

All participants must have an R0 resection, confirmed by a pathology report, meaning that the tumor was completely resected with no microscopic evidence of cancer cells at the tumor site.

What is the goal of this study? This study evaluates the efficacy of RO7198457 (autogene cevumeran), an individualized mRNA neoantigen vaccine, to prevent cancer recurrence compared to watchful waiting (standard of care).

What can patients expect? Participants are randomized to receive either:

1. RO7198457, a mRNA-based personalized vaccine (up to 15 doses given intravenously over 12 months)
2. Watchful waiting, also referred to as active surveillance (standard of care)

A prior trial using this vaccine determined that the vaccine does generate tumor-specific immune responses, and it is safe: most adverse events (AE) were grade 1-2. AEs occurring in ≥ 20% of patients included infusion related reaction (IRR)/cytokine release syndrome (CRS), fatigue, nausea, and diarrhea. IRR/CRS were transient and reversible and presented primarily as Grade 1-2 chills and fever. No patients discontinued due to AE.

What is being measured? The primary endpoint is disease-free survival.

Recently reported results (Abs 29P at ESMO, June 2024) from the biomarker cohort of the trial show that RO7198457 (autogene cevumeran) successfully stimulated the immune system to produce T-cells that recognize specific cancer markers in the 11 patients in this group. These T-cells made up a notable portion of the patients’ immune cells after 8 doses, with up to 42% (median: 9%, range: 3-42%) of circulating CD8+ T-cell receptors being vaccine-specific in 8 patients. All the patients remained disease-free at median follow-up of 640 days (range: 602–779 days).

It’s notable that all the patients remain NED, given the nature of stage II and stage III high risk CRC, where recurrence rates can be significant. However, as this was the biomarker cohort, it does not directly prove that the vaccine prevented recurrence compared to no intervention. The main trial, which includes a watchful waiting arm for ctDNA positive patients for comparison, will provide clarity on efficacy.

NCT06358430

This phase 1 active recruiting clinical trial explores a novel immunotherapy in CRC patients with MRD after surgery and standard adjuvant treatment.

Who is eligible? Colorectal cancer patients with MRD (defined as no evidence of radiological disease and a positive ctDNA test) following complete resection (surgery) and adjuvant therapy.

What is the goal of this study? This trial investigates the use of TROP2-CAR-NK cells, or TROP2 chimeric antigen receptor (CAR) engineered IL-15-transduced cord blood-derived natural killer (NK) cells (a type of adoptive cell therapy), combined with cetuximab (Erbitux®).

TROP2 is a protein often overexpressed in colorectal cancer. The therapy uses chimeric antigen receptor (CAR) technology to engineer NK cells —immune cells naturally equipped to kill cancer— to specifically recognize and attack TROP2-expressing cancer cells. The NK cells are modified with IL-15, a cytokine that boosts their survival and effectiveness, potentially making them better against residual cancer cells. The addition of standard of care cetuximab, that targets EGFR (another protein linked to CRC), may amplify the therapy’s impact.

The study aims to determine the highest and/or recommended dose of TROP2-CAR-NK cells in combination with cetuximab. It also seeks to assess the safety and tolerability of this combination therapy.

What can patients expect? This trial is a single-arm trial, meaning that all participants will receive the combination of TROP2-CAR-NK cells and cetuximab, both given intravenously.

What is being measured? Safety and adverse events are the primary focus. The study also measures circulating tumor DNA (ctDNA) clearance at 3 months, as an indicator of treatment effect.

If this therapy can eliminate hidden cancer cells, it could lower the chances of the disease returning, offering patients a better chance at long-term survival.

• Searching for trials and deciding on the right trial for you can take time. People interested in MRD trials should consider looking for them while they receive curative-intent treatment so that if they are ctDNA positive post-therapy, they can enroll in a MRD trial without much delay. There may also be opportunities for patients that are ctDNA negative to enroll in a clinical trial.
• It is important for patients that are ctDNA positive after curative-intent therapy to discuss getting a liver MRI with their healthcare provider before they decide to participate in a MRD trial (if a liver MRI is not part of the screening process for the trial). This is because an MRI may detect liver mets that a CT scan missed. Patients with a liver met may prefer to get local treatment, like surgery or ablation, to treat the lesion rather than enrolling in a clinical trial. Having this information can help patients make a more informed decision regarding their treatment.
• MRD trials may not be the best for everyone. By design, these trials may target patients with slow growing or indolent disease.

Our Clinical Trial Blog series unpacks important research trials, tips, and advice for our community. Be sure to subscribe to sign up with Fight CRC and join COLONTOWN’s online community to continue receiving the most relevant updates in the CRC world! You can also visit Fight CRC’s Clinical Trial Finder for more information on trials.