Chemotherapy Tailored by ctDNA Status for Colon Cancer

(CIRCULATE-US Trial)

Recruiting at 1072 trial locations

Overseen By Leon C. Hwang

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: NRG Oncology

Must not be taking: Antidepressants, Anticonvulsants

Disqualifiers: Metastatic disease, Prior chemotherapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6-12 cycles (approximately 3-6 months)

1912 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether chemotherapy should be customized for colon cancer patients based on their ctDNA (circulating tumor DNA) status after surgery. Researchers aim to determine if detecting ctDNA can guide the selection of the most effective chemotherapy plan. The trial compares different chemotherapy combinations, such as CAPOX, mFOLFIRINOX, and mFOLFOX6, or even the option of no treatment for certain patients. This trial may suit those with Stage IIB, IIC, or Stage III colon cancer who have undergone surgery to remove the tumor. As a Phase 2, Phase 3 trial, this research measures treatment effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on a coumarin-derivative anticoagulant, you must agree to weekly monitoring of INR if you are randomized to certain treatment arms.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the treatments studied in this trial have varying safety levels. For CAPOX, studies have found it effective for colon cancer patients, but risks exist. One study found that 30.7% of patients experienced serious side effects, such as severe diarrhea or low blood counts, which could lead to hospitalization.

The mFOLFIRINOX treatment, another option explored, also presents significant side effects. Research indicates that more than half of the patients experienced serious side effects, including nausea, vomiting, or fatigue. These side effects occur more frequently than with other treatments.

Both treatments have been used for colon cancer before, so doctors have experience with them. However, they can cause strong side effects. Anyone considering joining a trial should carefully consider these risks and discuss them with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for colon cancer because they are tailored based on ctDNA (circulating tumor DNA) status, allowing for more personalized care. Unlike traditional chemotherapy, which is often a one-size-fits-all approach, these treatments adjust the intensity and type of therapy according to the presence or absence of ctDNA. This approach could potentially minimize unnecessary treatment for patients without detectable ctDNA, reducing side effects, while intensifying therapy for those with ctDNA to target residual disease more effectively. Additionally, the use of the Signatera test for serial ctDNA monitoring enables real-time tracking of the cancer's response to treatment, offering a dynamic way to adjust therapy as needed.

What evidence suggests that this trial's treatments could be effective for colon cancer?

Research has shown that CAPOX, a combination of the chemotherapy drugs capecitabine and oxaliplatin, works well for patients with high-risk stage II and stage III colon cancer. It is cost-effective compared to treatments like FOLFOX. In this trial, participants in Cohort A - Arm 1 (ctDNA-ve) and Cohort B - Arm 3 (ctDNA+ve) may receive CAPOX as part of their treatment regimen. Another treatment, mFOLFOX6, has helped patients with stage III colon cancer live longer, especially those with certain tumor types. It also improves outcomes for patients with metastatic colorectal cancer when oxaliplatin is included. Participants in Cohort A - Arm 1 (ctDNA-ve) and Cohort B - Arm 3 (ctDNA+ve) may also receive mFOLFOX6. Meanwhile, mFOLFIRINOX has shown promise in extending the time patients remain free of disease. One study reported an average disease-free period of 21.4 months, longer than with treatments like gemcitabine. Participants in Cohort B - Arm 4 (ctDNA+ve) may receive mFOLFIRINOX. Each of these treatments has its own strengths and is effective for different patient needs in colon cancer. ^{2 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with colon adenocarcinoma who've had surgery, no metastatic disease, and a good performance status. They must be able to take chemo drugs like 5FU and oxaliplatin, have stable HIV if present, not be pregnant or breastfeeding, and agree to ctDNA testing using the Signatera test.

Inclusion Criteria

I can receive treatments like 5FU, LV, oxaliplatin, and irinotecan.

I am HIV-positive, on treatment, and my viral load is undetectable.

Developed a ctDNA +ve assay during serial monitoring

Exclusion Criteria

My colon cancer is not adenocarcinoma.

My cancer has spread to other parts of my body.

My cancer has caused a hole in my intestine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive adjuvant chemotherapy based on ctDNA status. Options include Oxaliplatin, Leucovorin, 5-Fluorouracil, and Capecitabine regimens.

6-12 cycles (approximately 3-6 months)

Follow-up

Participants are monitored for disease-free survival, recurrence, and overall survival.

5 years

Serial ctDNA Monitoring

Participants undergo serial ctDNA monitoring to assess recurrence risk and treatment efficacy.

Throughout the trial

What Are the Treatments Tested in This Trial?

Interventions

• CAPOX
• mFOLFIRINOX
• mFOLFOX6
• Signatera test

Trial Overview The study tests different chemotherapy durations (3-6 months) using mFOLFOX6 or CAPOX based on circulating tumor DNA presence after colon cancer surgery. It aims to tailor post-surgery chemo treatment more effectively.

How Is the Trial Designed?

Group I: Cohort B - Arm 4 (ctDNA+ve) Experimental Treatment 2 Interventions

Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + Irinotecan 150 mg/m2 IV continuous infusion (30-90 minutes) + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles

Group II: Cohort A - Arm 2 (ctDNA-ve) Experimental Treatment 1 Intervention

Serial ctDNA monitoring no treatment

Group III: Cohort A - Arm 1 (ctDNA-ve) Active Control 3 Interventions

Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 6-12 cycles OR Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 4 cycles

Group IV: Cohort B - Arm 3 (ctDNA+ve) Active Control 3 Interventions

Oxaliplatin 85 mg/m2 IV + Leucovorin 400mg/m2 IV + 5-Fluorouracil (5-FU) 400mg/m2 bolus + 5-Fluorouracil (5-FU) 2400mg/m2 IV continuous infusion over 46-48 hours (total dose) Day1 every 2 weeks for 12 cycles OR Oxaliplatin 130 mg/m2 IV Day 1 every 3 weeks + Capecitabine 1000 mg/m2 BID by mouth days 1-14 every 3 weeks for 8 cycles

Who Is Running the Clinical Trial?

NRG Oncology

Lead Sponsor

Trials

242

Recruited

105,000+

Natera, Inc.

Industry Sponsor

Trials

56

Recruited

50,700+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Circulating tumor DNA (ctDNA) is becoming a valuable tool in precision oncology for diagnosing and managing cancer, with FDA-approved assays enhancing the safe use of targeted therapies.

ctDNA is particularly useful for detecting molecular residual disease (MRD) in early-stage solid tumors, which can help guide timely treatment decisions to prevent metastasis, although further standardization and validation of ctDNA assays are needed for regulatory use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory implications of ctDNA in immuno-oncology for solid tumors. Vellanki, PJ., Ghosh, S., Pathak, A., et al.[2023]

In a study of 69 patients with resected metastatic colorectal cancer (mCRC), the use of a personalized circulating tumor DNA (ctDNA) assay showed that MRD positivity is strongly linked to poorer disease-free survival (DFS) and overall survival (OS), indicating its potential as a prognostic tool.

The ctDNA assay demonstrated high specificity (100%) and moderate sensitivity (69%) for detecting MRD, suggesting it could effectively guide treatment decisions for high-risk patients post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive Genomic Profiling (CGP)-Informed Personalized Molecular Residual Disease (MRD) Detection: An Exploratory Analysis from the PREDATOR Study of Metastatic Colorectal Cancer (mCRC) Patients Undergoing Surgical Resection. Lonardi, S., Nimeiri, H., Xu, C., et al.[2023]

In a study of 93 metastatic colorectal cancer patients receiving cetuximab-containing chemotherapy, the presence of KRAS or NRAS mutations in circulating tumor DNA (ctDNA) was linked to significantly worse progression-free survival (PFS).

Changes in the variant allele frequency (VAF) of ctDNA correlated with tumor size changes, and patients whose VAF decreased below 1% at the first evaluation experienced significantly better PFS, indicating that ctDNA analysis can be a valuable tool for monitoring treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR. Lim, Y., Kim, S., Kang, JK., et al.[2021]

In a case series of 3 patients with advanced colorectal cancer, those treated with neoadjuvant and adjuvant immunotherapy (sintilimab and toripalimab) showed promising progression-free survival (PFS) rates of over 16 to 17 months, indicating potential efficacy of PD-1 blockade in this setting.

All patients had detectable circulating tumor DNA (ctDNA) after surgery, but showed clearance of ctDNA during adjuvant therapy, suggesting that ctDNA monitoring could be a valuable tool in assessing treatment response and long-term outcomes in immunotherapy for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serial Circulating Tumor DNA in Monitoring the Effect of Neoadjuvant and Adjuvant Immunotherapy in Patients With Colon Cancer: Case Series and Review of the Literature. Qin, Q., Yang, K., Ma, T., et al.[2022]

In a study of 20 patients with advanced colorectal cancer treated with regorafenib, over 50% of tumor-specific mutations were also found in baseline plasma samples, highlighting the potential of using circulating tumor DNA (ctDNA) as a biomarker.

High levels of baseline cell-free DNA (cfDNA) and early increases in mutated ctDNA levels were strongly associated with poorer overall survival and progression-free survival, suggesting that monitoring ctDNA could be a valuable tool for predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating tumor DNA in early response assessment and monitoring of advanced colorectal cancer treated with a multi-kinase inhibitor. Vandeputte, C., Kehagias, P., El Housni, H., et al.[2019]

In a study of 48 patients with resected colorectal cancer, the ctDNA assay did not show superior sensitivity compared to standard imaging techniques for detecting disease recurrence, with sensitivities of 53.3% for ctDNA and 60.0% for imaging.

The combination of imaging and carcinoembryonic antigen (CEA) measurement had a higher sensitivity of 73.3% for identifying recurrences, suggesting that ctDNA may not be a more effective surveillance strategy than existing methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Comparative Surveillance Strategies of Circulating Tumor DNA, Imaging, and Carcinoembryonic Antigen Levels in Patients With Resected Colorectal Cancer. Fakih, M., Sandhu, J., Wang, C., et al.[2022]

In a study of 82 patients with metastatic colorectal cancer (mCRC), high levels of circulating tumor DNA (ctDNA) before treatment were associated with significantly shorter overall survival, indicating that ctDNA concentration can be a critical marker for prognosis.

Patients classified as 'good ctDNA responders' based on early changes in ctDNA levels had a much better response to chemotherapy, with longer progression-free survival (8.5 months) and overall survival (27.1 months) compared to 'bad ctDNA responders', highlighting the potential of ctDNA as a predictive biomarker for treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study). Garlan, F., Laurent-Puig, P., Sefrioui, D., et al.[2018]

In a study of metastatic colorectal cancer patients undergoing second-line chemotherapy, a significant decrease in circulating tumor DNA (ctDNA) levels after 8 weeks was associated with longer progression-free survival (PFS) and overall survival (OS), indicating its potential as a predictive biomarker.

Patients with lower ctDNA levels (≤50%) after treatment had better clinical outcomes compared to those with higher levels (>50%), suggesting that monitoring ctDNA changes can help assess the effectiveness of chemotherapy early on.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer. Osumi, H., Shinozaki, E., Yamaguchi, K., et al.[2021]

Circulating tumor DNA (ctDNA) is emerging as a promising biomarker for assessing minimal residual disease (MRD) in patients with resected colorectal cancer, potentially offering more precise risk stratification than traditional methods.

Current studies suggest that ctDNA could outperform existing clinicopathologic criteria in identifying patients with MRD, and ongoing clinical trials aim to validate ctDNA-guided treatment strategies that could significantly change how adjuvant therapy is administered for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Finding Waldo: The Evolving Paradigm of Circulating Tumor DNA (ctDNA)-Guided Minimal Residual Disease (MRD) Assessment in Colorectal Cancer (CRC). Chakrabarti, S., Kasi, AK., Parikh, AR., et al.[2022]

In a case study of an 81-year-old woman with metastatic colorectal cancer, ctDNA testing revealed a high microsatellite instability (MSI-H) and a BRAF mutation that were not detected by traditional tissue genomic profiling, leading to a change in treatment strategy.

The addition of the immunotherapy nivolumab to the chemotherapy regimen resulted in a complete clinical response after 8 months, demonstrating the potential of ctDNA testing to uncover actionable biomarkers that can significantly improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Tumor DNA Testing Overcomes Limitations of Comprehensive Genomic Profiling from Tumor Tissue. Kumar, A., Green, M., Thacker, J., et al.[2023]

In a study of 78 patients with advanced colorectal cancer, over 80% had detectable circulating tumor DNA (ctDNA) alterations, with most having actionable mutations that could be targeted by FDA-approved drugs or experimental therapies.

The study found a concordance rate of 62% to 87% between ctDNA and tissue genomic alterations, indicating that ctDNA profiling can effectively guide treatment decisions and monitor resistance to therapies, particularly in patients receiving anti-EGFR treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Colorectal Cancer: Implications for Response and Resistance to Targeted Therapeutics. Choi, IS., Kato, S., Fanta, PT., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7842523/

Efficacy and Safety of Capecitabine and Oxaliplatin ... CapOX therapy as an adjuvant chemotherapy for groups at high risk of recurrence of stage II and stage III colon cancer has been demonstrated to be excellent.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.90

Real-world assessment of capecitabine and oxaliplatin ... Among patients intended to receive 4 cycles of CAPOX, only 57% (37/65) completed all 4 cycles. Female patients were less likely to complete ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6567718/

Retrospective comparison of efficacy and safety of CAPOX ... In a study by Aitini et al., the CAPOX regimen was more cost-effective compared with the FOLFOX regimen, as the adjuvant treatment of colon cancer. Therefore, ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1533002825000271

Treatment adherence to adjuvant chemotherapy according ... In total, 802 (80.0%) of the 1002 patients completed 4 cycles of CAPOX. The overall mean RDI of adjuvant treatment was 82.9% for capecitabine, ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1713709

Duration of Adjuvant Chemotherapy for Stage III Colon ... Overall, about 40% of patients received CAPOX, and 60% FOLFOX. Table S3 in the Supplementary Appendix lists the characteristics of the patients ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2059702920323292

Safety data from the phase III Japanese ACHIEVE trial: part ... ACHIEVE was an open-label, multicentre trial randomising patients with stage III colon cancer to receive 3 m or 6 m of mFOLFOX6/CAPOX after surgery. Choice of ...

7. journals.lww.com journals.lww.com/indianjcancer/fulltext/2022/59010/efficacy_and_safety_of_capecitabine_and.11.aspx

Efficacy and safety of capecitabine and oxaliplatin (CAPOX ... CAPOX regimen was found to be effective in the management of colorectal cancer in a real world nonclinical trial setting. The toxicities associated with the ...

8. ascopubs.org ascopubs.org/doi/abs/10.1200/OP-24-00647

Real-World Tolerability of Capecitabine and Oxaliplatin in ... The rate of grade ≥3 adverse events and hospitalization because of CAPOX-related toxicity were 30.7% (95% CI, 23 to 38) and 17.6% (95% CI, 11 to ...