Chemotherapy Tailored by ctDNA Status for Colon Cancer

(CIRCULATE-US Trial)

Recruiting at 965 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

Trial Summary

What is the purpose of this trial?

This trial tests if a blood test for cancer DNA can help decide if colon cancer patients need more treatment after surgery. The test looks for cancer DNA in the blood to predict if the cancer might come back and to guide further treatment.

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.

What data supports the effectiveness of the treatment tailored by ctDNA status for colon cancer?

Research suggests that changes in circulating tumor DNA (ctDNA) levels can predict how well chemotherapy will work for patients with metastatic colorectal cancer. Patients with lower ctDNA levels after starting chemotherapy tend to have better outcomes, such as longer survival and slower disease progression. ^{1 2 3 4 5}

Is ctDNA testing safe for humans?

Circulating tumor DNA (ctDNA) testing is considered safe as it is a noninvasive method that involves a routine blood draw to analyze tumor DNA, and it has been approved by the US Food and Drug Administration for use with certain therapies. ^{1 6 7 8 9}

How does the ctDNA-guided chemotherapy treatment for colon cancer differ from other treatments?

This treatment is unique because it uses circulating tumor DNA (ctDNA) to tailor chemotherapy for colon cancer patients, allowing for personalized treatment adjustments based on the presence of minimal residual disease (MRD). This approach aims to improve treatment outcomes by identifying patients who may benefit from more or less aggressive therapy, unlike traditional methods that rely solely on tumor characteristics. ^{1 4 5 10 11}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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]

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 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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR. [2021]

2. United States 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. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Circulating tumor DNA in early response assessment and monitoring of advanced colorectal cancer treated with a multi-kinase inhibitor. [2019]

4. Switzerland 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. [2023]

5. England 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. [2021]

6. United States 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. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Regulatory implications of ctDNA in immuno-oncology for solid tumors. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Circulating Tumor DNA Testing Overcomes Limitations of Comprehensive Genomic Profiling from Tumor Tissue. [2023]

9. United States 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. [2020]

10. Switzerland 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). [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study). [2018]