Clinical Trials for Early-Stage Colorectal Cancer or Minimal Residual Disease

March 29, 2023 • By Fight CRC

Clinical Trial Conversations
hero symbol

This month we revisit some clinical trials for early-stage colorectal cancer and for patients with minimal residual disease (MRD). Early-stage colorectal cancer refers to colorectal cancer diagnosed at stage I-III, which has not metastasized or spread to other parts of the body. MRD describes microscopic residual disease, where a very small number of cancer cells may remain in the body during or after treatment. Minimal residual disease can be found only by highly sensitive laboratory methods that are able to detect very small proportions of cancer cells.

Manju:

The use of circulating tumor DNA (ctDNA) is becoming more widespread and for early-stage colorectal cancer patients who are interested in having ctDNA testing as part of their cancer journey, there are many currently enrolling trials available, which I will outline below.

Circulating Tumor DNA Testing in Predicting Treatment for Patients With Stage IIa Colon Cancer After Surgery (COBRA)

NCT04068103

This currently enrolling stage II colon cancer ctDNA trial (532/1408 slots already filled) is open in both the U.S. and Canada at 907 locations.

This phase 2/3 trial looks at how well ctDNA testing can be used to predict treatment for patients with stage IIa colon cancer after surgery. Testing for ctDNA could help identify patients with colon cancer after surgery who do benefit, and those who do not benefit, from receiving chemotherapy.

Stage IIa colon cancer patients who have their primary colon tumor removed are randomized to one of two arms.

In arm 1, blood will be collected for ctDNA testing, but the test will be done later and patients will  undergo active surveillance (current standard of care for this group of patients).

In arm 2, blood will be collected and tested for ctDNA. Based on the ctDNA status, if positive, they will receive adjuvant chemotherapy (up to 12 cycles of FOLFOX or eight cycles of CAPOX). If the ctDNA test is negative, they will have active surveillance similar to patients in arm 1.

In the Phase 2 part of the trial, they will compare the rate of ctDNA clearance in ctDNA positive patients treated with or without adjuvant chemotherapy. This will tell us the role of chemotherapy in clearing ctDNA.

In the Phase 3 part, they will compare recurrence-free survival (RFS) in ctDNA positive patients treated with or without adjuvant chemotherapy following resection of stage IIa colon cancer. This will tell us the role of chemotherapy in preventing recurrence in ctDNA positive patients.

Colon Adjuvant Chemotherapy Based on Evaluation of Residual Disease (CIRCULATE-US)

NCT05174169

CIRCULATE-US (soon to open in Canada as well) is a large currently enrolling (39/1910 slots filled) phase 2/3 trial for early-stage colon cancer patients. 

This is a large randomized trial to evaluate the kind of chemotherapy to recommend for stage 2/3 colon cancer patients with presence or absence of ctDNA after surgery. In the trial, patients will get tested for ctDNA using the tumor-informed SignateraTM test (a tumor-informed ctDNA or liquid biopsy test, is a laboratory test done on a sample of blood to look for small pieces of DNA released by tumor cells into a person’s blood. Such a test allows multiple samples to be taken over time, which may help doctors understand what kind of genomic or molecular changes are taking place in a tumor. Such a test can detect molecular or minimal residual disease, which is microscopic disease that may be left behind in the body after surgical removal of the tumor.). 

To be eligible, patients must have colon cancer (T1-3, N1/N1c) with successful surgical removal of the primary tumors with clear margins. Patients with stage II or IIIc colon cancer who are ctDNA positive on a Signatera test outside of the trial and are ctDNA positive after surgery and meet all timelines and eligibility requirements are eligible to enroll and will be included in cohort B.

Those who are ctDNA negative will be part of cohort A where they are randomized to serial ctDNA monitoring without adjuvant chemo (experimental, arm 2) or to six-12 cycles of FOLFOX or four cycles of CAPOX (standard of care arm 1).

So this is a great trial to consider for patients with a ctDNA positive result after surgery, and this trial will be open at many locations throughout the U.S.

The primary endpoints include: TTpos, which is time to a positive ctDNA test. TTPos events are first ctDNA positive result after randomization for arm 1, second ctDNA positive result after randomization in arm 2 and recurrence without a positive ctDNA result for both arms. Disease free survival (DFS) is another primary endpoint.

Patients who test ctDNA positive at any time point in cohort A are allowed to cross over to cohort B, which is for patients who are ctDNA positive. In this cohort, patients are randomized to:

1) 12 cycles of FOLFOX or eight cycles of CAPOX (standard of care arm) 

Or 

2) 12 cycles of FOLFIRINOX

The idea behind the trial is that colon cancer patients who do not have detectable ctDNA (ctDNA-) are at a much lower risk for recurrence and may not need adjuvant chemotherapy. On the other hand, colon cancer patients with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence may need more aggressive adjuvant chemotherapy regimens than are currently used. In this trial, the hypothesis is that for patients whose colon cancer has been removed by surgery, ctDNA status may be used for risk stratification for making decisions about adjuvant chemotherapy.

Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer (ACT3)

NCT03803553

The above two trials are for early-stage colon cancer patients where the ctDNA test result status is used to inform the kind of adjuvant chemotherapy they would receive.

What if you are a stage III colon cancer patient who has completed surgery and adjuvant chemotherapy, and are now ctDNA positive? Or if you are a stage III patient with a cancer that has a high chance of recurrence (example: stage IIIc, your tumor has a BRAF mutation, etc.), is there a trial for you where you can get different treatment options if ctDNA positive?

The ACT3 trial is a trial that you could consider. Maia has more trials for ctDNA positive patients below.

The 500-patient, Stand Up To Cancer ACT3 ctDNA trial is for stage III colon cancer patients who have recently completed surgery and adjuvant chemotherapy treatments. On the trial, they will get tested for ctDNA and if positive, they are randomized to: 1) active surveillance, or 2) be eligible based on their tumor characteristics to receive either the next line of chemotherapy (FOLFIRI), or targeted therapy (if BRAF mutated or HER2 amplified) or immunotherapy if MSI-H. Those who test ctDNA negative will have active surveillance recommended for stage III patients. The purpose of the trial is to figure out if there are differences in cancer recurrence and health between ctDNA positive patients on active surveillance versus more treatments, and how more treatments affect ctDNA levels. The trial is now open at Massachusetts General Hospital, Memorial Sloan Kettering Cancer Center, Cornell, Dana-Farber Cancer Institute, and Johns Hopkins.

Maia:

All those trials that you covered, Manju, are a perfect example of how liquid biopsies already have, at the present, a role in the clinical trials setting.

I’d like to highlight some clinical trials for early-stage and/or MRD that involve immunotherapy: therapeutic vaccines and adoptive cell therapy. 

These four trials are for MRD, which is defined as the lack of radiographically evident disease in the presence of ctDNA that matches the original tumor mutations (a positive liquid biopsy), and/or elevated serum tumor biomarkers, like carcinoembryonic antigen (CEA). Then, we continue talking about liquid biopsies here, since this remarkable tool is used in all the following trials to select patients who might benefit from the novel treatments being investigated.

Phase 2 Clinical Trial Comparing the Efficacy of RO7198457 Versus Watchful Waiting in Patients with ctDNA-positive, Resected Stage II (High Risk) and Stage III Colorectal Cancer

NCT04486378

This clinical trial is for patients with stage II or III rectal or colon cancer who recently had surgery and whose ctDNA (liquid biopsy) test came positive after resection, which may be an indicator of higher risk of recurrence. Only those diagnosed with MSS (microsatellite stable) tumors are allowed to participate.

The trial is randomized: Some patients receive the vaccine, while others the standard of care, and they are assigned to either arms by chance. Patients in the experimental arm receive a personalized cancer vaccine, mRNA-based (iNeST RO7198457; Autogene cevumeran), given intravenously, over 12 months. Outcomes for these patients will be compared to results from the patients receiving the standard of care – the “watchful waiting” approach. 

A prior trial with this vaccine determined that the vaccine does generate tumor-specific immune responses, and it is safe. The vaccine may have a role when used to prevent recurrence with no active disease. This trial looks forward to answering that question and, hopefully, helping many patients to maintain no evidence of disease (NED).

This is a multicenter clinical trial, ongoing at several locations across the U.S. and Europe.

ELI-002 in Subjects with KRAS Mutated Pancreatic Ductal Adenocarcinoma (PDAC) and Other Solid Tumors (AMPLIFY-201)

NCT04853017  

This study is directed only to those diagnosed with KRAS or NRAS mutant cancer, already treated, with no evidence of disease in images but with MRD; a positive ctDNA; or elevated tumor markers (CEA). The record doesn’t specifically mention stages.

The trial aims to recruit 18 patients across the U.S. to receive a novel therapeutic vaccine, ELI-002, to treat a KRAS or NRAS mutated (G12D or G12R) solid tumor, including colon and rectal cancers.

ELI-002 is a structurally novel amphiphile (AMP) therapeutic vaccine targeting KRAS-driven cancers. The AMP platform is intended to deliver conventional immunomodulatory vaccines directly and preferentially to the lymph node, which can facilitate interaction with the various components of the adaptive immune system. 

Immunotherapy may succeed in the MRD setting, inducing more effector T cells to target the tumor cells before there is bulk, visible disease.

EO2040 in Combination with Nivolumab, for Treatment of Patients with Minimal Residual Disease of Colorectal Cancer (CLAUDE)

NCT05350501

CLAUDE is an ongoing study only at MD Anderson in Texas. It looks to evaluate the combination of two immunotherapies to prevent the cancer from recurring, for patients with stage II, III, or IV colorectal cancer who have completed standard, curative therapy and have a positive ctDNA.

34 patients will receive the microbiome-derived therapeutic vaccine EO2040 along with nivolumab (a PD-1 checkpoint inhibitor, Opdivo®), in the case they have MRD, defined by the presence of a positive liquid biopsy, as mentioned above. It’s remarkable the inclusion of stage IV NED patients, who very often are interested in participating in a clinical trial that doesn’t involve chemotherapy to keep their “clean scans” status.

The combination of this vaccine with nivolumab has been already tested in clinical trials for other cancers (glioblastoma and adrenal tumors) and shown to be safe and well-tolerated.

Phase 1b Study of Immunotherapy with Ex Vivo Pre-activated and Expanded CB-NK Cells in Combination with Cetuximab, in Colorectal Cancer Patients with Minimal Residual Disease (MRD)

NCT0504056

This is another clinical trial only taking place at MD Anderson. It is the only research study that we are covering in this blog that involves other type of immunotherapy than vaccines and checkpoint inhibitors: adoptive cells transfer.

In this Phase Ib trial, expanded cord blood (CB) NK cells are given in combination with cetuximab (Erbitux®), both intravenously, to colorectal cancer patients who are NED and at high risk of recurrence.

This study aims to enroll 15 patients, with stage II or III, and resected stage IV colorectal cancer and positivity for MRD, a lack of radiographically evident disease, in the presence of positive ctDNA that matches the original tumor mutations.

The primary goal of the study is “ctDNA clearance from the blood.” In other words, the combination is meant to not only maintain “NED” but also to achieve a negative ctDNA result.

Stay Tuned for More!

Once a month, Maia and Manju spend time unpacking 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 follow Maia (@sassycell) and Manju (@manjuggm) to stay updated on research and trials and visit ClinicalTrials.gov for more information on trials.

Clinical trials are critical to finding a cure for colorectal cancer. As an advocacy organization dedicated to supporting and empowering a community of patients, caregivers and families, Fight CRC has partnered with COLONTOWN to deliver a monthly blog series highlighting everything patients need to know about clinical trials and the best treatment options available. 

In this series, we hope to cover promising trials that are enrolling, lessons learned from past research, logistics and resources to joining a clinical trial, and provide relevant and timely updates for our colon and rectal cancer community. 

Be Sure to Check Out These Fight CRC Resources:

Clinical Trial Finder

More Clinical Trial Conversations