Chemotherapy Tailored by ctDNA Status for Colon Cancer (CIRCULATE-US Trial)
Recruiting in Palo Alto (17 mi)
+951 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: NRG Oncology
No Placebo Group
Prior Safety Data
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.
12345Is 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.
16789How 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.
1451011Eligibility 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 am fully active or can carry out light work.
My colon cancer was confirmed by a lab test and has been fully removed by surgery.
My tumor is located more than 12 cm from the anal opening or above the peritoneal reflection.
My tumor was completely removed in one piece.
My tumor is not affected by certain genetic instabilities.
I can receive treatments like 5FU, LV, oxaliplatin, and irinotecan.
I can provide tissue samples from my surgery for further testing.
I am fully active or can carry out light work.
My blood, liver, and kidney tests are normal.
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.
I have had colon cancer before.
I have had a bone marrow or organ transplant.
I have had chemotherapy, targeted therapy, immunotherapy, or radiation for colorectal cancer.
I have not had any other cancer besides this one in the last 5 years.
I have cancer in both my rectum and colon at the same time.
My heart condition limits my physical activity.
I have moderate to severe numbness, tingling, or muscle weakness.
I have seizures that medication does not control.
I am currently on medication for a long-term infection.
I have a confirmed DPD deficiency.
I have Gilbert's Syndrome or a specific genetic condition (UGT1A1*28).
Participant Groups
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.
4Treatment groups
Experimental Treatment
Active Control
Group I: Cohort B - Arm 4 (ctDNA+ve)Experimental Treatment2 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 Treatment1 Intervention
Serial ctDNA monitoring no treatment
Group III: Cohort A - Arm 1 (ctDNA-ve)Active Control3 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 Control3 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
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
McFarland Clinic PC-JeffersonJefferson, IA
Kaiser Permanente-Santa Teresa-San JoseSan Jose, CA
Northwestern UniversityChicago, IL
Norton Hospital Pavilion and Medical CampusLouisville, KY
More Trial Locations
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Who is running the clinical trial?
NRG OncologyLead Sponsor
Natera, Inc.Industry Sponsor
National Cancer Institute (NCI)Collaborator
References
Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR. [2021]Circulating tumor DNA (ctDNA) may reveal dynamic tumor status during therapy. We conducted serial ctDNA analysis to investigate potential association with clinical outcome in metastatic colorectal cancer (mCRC) patients receiving chemotherapy. Tissue KRAS/NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy. ctDNA isolated from plasma were analyzed by next generation sequencing (NGS) with 16 targeted gene panel. Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) (p = 0.029). Changes in average variant allele frequency (VAF) in ctDNA showed significant correlation with tumor size change at the time of first response evaluation (p = 0.020) and progressive disease (PD) (p = 0.042). Patients whose average VAF decreased below cutoff (
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]Although programmed death 1 blockade has significantly improved the survival of advanced colorectal cancer patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H), clinical data in neoadjuvant and adjuvant setting are limited. The role of circulating tumor DNA (ctDNA) in precision oncology is promising, but its clinical significance in immunotherapy needs to be validated. We report a case series of 3 colon patients who received neoadjuvant and adjuvant immunotherapy and serial ctDNA analysis. This report summarizes clinical and molecular details for 3 patients with locally advanced or recurrent dMMR/MSI-H/polymerase epsilon ( POLE ) mutation-positive tumors treated with neoadjuvant/adjuvant immunotherapy. One stage IV recurrent colon cancer patient diagnosed with Lynch syndrome received adjuvant sintilimab monotherapy and had a progression-free survival (PFS) over 16 months, one stage Ⅲc colon cancer patient with MSI-H/high tumor mutation burden received neoadjuvant toripalimab monotherapy, was assessed as clinical complete response before surgery, continued with adjuvant sintilimab monotherapy and had a PFS over 17 months, one stage Ⅱ colon cancer patient with POLE P286R also received adjuvant sintilimab monotherapy and had a PFS over 17 months. All patients had detectable ctDNA after radical surgery and clearance of ctDNA during adjuvant immunotherapy. All 3 patients are free of tumor disease at the time of this report. Further studies are warranted to evaluate the long-term efficacy of neoadjuvant and adjuvant programmed death 1 blockade in locally advanced and metastasis in dMMR/MSI-H/ POLE mutated colorectal cancer and the role of ctDNA monitoring.
Circulating tumor DNA in early response assessment and monitoring of advanced colorectal cancer treated with a multi-kinase inhibitor. [2019]Predictive biomarkers are eagerly awaited in advanced colorectal cancer (aCRC). Targeted sequencing performed on tumor and baseline plasma samples in 20 patients with aCRC treated with regorafenib identified 89 tumor-specific mutations of which ≥50% are also present in baseline plasma. Droplet digital PCR (ddPCR) assays were optimized to monitor circulating tumor DNA (ctDNA) levels in plasmatic samples collected throughout the treatment course and showed the importance of using the absolute value for ctDNA rather than the mutant/wild type ratio in monitoring the therapy outcome. High baseline cell free DNA (cfDNA) levels are associated with shorter overall survival (OS) (HR 7.38, P=0.001). An early increase (D14) in mutated copies/mL is associated with a significantly worse PFS (HR 6.12, P=0.008) and OS (HR 8.02, P=0.004). These data suggest a high prognostic value for early ctDNA level changes and support the use of blood-born genomic markers as a tool for treatment.
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]A majority of patients with metastatic colorectal cancer (mCRC) experience recurrence post curative-intent surgery. The addition of adjuvant chemotherapy has shown to provide limited survival benefits when applied to all patients. Therefore, a biomarker to assess molecular residual disease (MRD) accurately and guide treatment selection is highly desirable for high-risk patients. This feasibility study evaluated the prognostic value of a tissue comprehensive genomic profiling (CGP)-informed, personalized circulating tumor DNA (ctDNA) assay (FoundationOne®Tracker) (Foundation Medicine, Inc., Cambridge, MA, USA) by correlating MRD status with clinical outcomes. ctDNA analysis was performed retrospectively on plasma samples from 69 patients with resected mCRC obtained at the MRD and the follow-up time point. Tissue CGP identified potentially actionable alterations in 54% (37/69) of patients. MRD-positivity was significantly associated with lower disease-free survival (DFS) (HR: 4.97, 95% CI: 2.67−9.24, p
Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer. [2021]The impact of ctDNA changes after chemotherapy on the clinical outcomes of patients with metastatic colorectal cancer (mCRC) remains unclear. The present study evaluated the clinical implications of the early change in ctDNA levels as a predictor of objective response and clinical outcome in mCRC patients who received chemotherapy. We investigated the effects of after/before ratio of ctDNA levels 2 and 8 weeks after initiation of second-line chemotherapy, on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). ctDNA was detected using amplicon-based deep sequencing with a molecular barcode encompassing >240 hotspot mutations in 14 colon cancer-related genes. In multivariate analysis, as compared to baseline, patients with lower ctDNA level (≤50%) 8 weeks after initiation of chemotherapy showed significantly longer PFS and OS than the patients with higher (>50%) ctDNA level. In patients achieving a partial response or stable disease, the after/before ratio of ctDNA level 8 weeks after initiation of chemotherapy was significantly lower than those in patients with progressive disease. The present study suggests that an early change in the ctDNA level might serve as a biomarker to predict the chemotherapeutic efficacy and clinical outcomes in patients with mCRC.
Evaluation of Comparative Surveillance Strategies of Circulating Tumor DNA, Imaging, and Carcinoembryonic Antigen Levels in Patients With Resected Colorectal Cancer. [2022]A circulating tumor DNA (ctDNA) assay (Signatera; Natera) has been marketed for use in the surveillance of resected colorectal cancer despite limited data supporting such practice.
Regulatory implications of ctDNA in immuno-oncology for solid tumors. [2023]In the era of precision oncology, use of circulating tumor DNA (ctDNA) is emerging as a minimally invasive approach for the diagnosis and management of patients with cancer and as an enrichment tool in clinical trials. In recent years, the US Food and Drug Administration has approved multiple ctDNA-based companion diagnostic assays for the safe and effective use of targeted therapies and ctDNA-based assays are also being developed for use with immuno-oncology-based therapies. For early-stage solid tumor cancers, ctDNA may be particularly important to detect molecular residual disease (MRD) to support early implementation of adjuvant or escalated therapy to prevent development of metastatic disease. Clinical trials are also increasingly using ctDNA MRD for patient selection and stratification, with an ultimate goal of improving trial efficiency through use of an enriched patient population. Standardization and harmonization of ctDNA assays and methodologies, along with further clinical validation of ctDNA as a prognostic and predictive biomarker, are necessary before ctDNA may be considered as an efficacy-response biomarker to support regulatory decision making.
Circulating Tumor DNA Testing Overcomes Limitations of Comprehensive Genomic Profiling from Tumor Tissue. [2023]"Liquid biopsy" is an established technique for examining circulating tumor DNA (ctDNA) from a routine blood draw and detecting actionable biomarkers. Nonetheless, ctDNA testing is rarely utilized for patients with newly diagnosed metastatic colorectal cancer (CRC). We report a case in which ctDNA testing uncovered an actionable biomarker that was not detected by comprehensive genomic profiling of tumor tissue. An 81-year-old woman with a remote history of non-Hodgkin's lymphoma presented with primary masses in the ascending colon and sigmoid colon. The ascending colon and sigmoid colon tumors were classified as microsatellite stable (MSS) and mismatch repair proficient (pMMR), and both ctDNA and tissue next-generation sequencing (NGS) from the ascending colon mass were ordered. Because tissue NGS results indicated that the ascending colon tumor was MSS, palliative 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy was started. However, the ctDNA NGS results that arrived after the start of FOLFOX found high microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR) disease with a serine/threonine-protein kinase B-Raf (BRAF V600E ) mutation. To treat both her MSS/pMMR ascending colon and sigmoid colon tumors and MSI-H/dMMR metastatic disease, the immunotherapy nivolumab was added to FOLFOX. After 8 months of combined nivolumab and chemotherapy, the patient's metastatic disease had a complete clinical response. This case highlights the complementary role of ctDNA testing for biomarker identification. By performing simultaneous ctDNA testing at the time of diagnosis, an actionable biomarker was discovered that significantly altered this patient's prognosis and treatment options. Orthogonal testing of key molecular alterations offers significant advantages for identifying actionable biomarkers and improving management of metastatic CRC.
Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Colorectal Cancer: Implications for Response and Resistance to Targeted Therapeutics. [2020]Molecular profiling of circulating tumor DNA (ctDNA) is a promising noninvasive tool. Here, next-generation sequencing (NGS) of blood-derived ctDNA was performed in patients with advanced colorectal cancer. We investigated ctDNA-derived genomic alterations, including potential actionability, concordance with tissue NGS, and serial dynamics in 78 patients with colorectal cancer using a clinical-grade NGS assay that detects single nucleotide variants (54-73 genes) and selected copy-number variants, fusions, and indels. Overall, 63 patients [80.8% (63/78)] harbored ctDNA alterations; 59 [75.6% (59/78)], ≥1 characterized alteration (variants of unknown significance excluded). All 59 patients had actionable alterations potentially targetable with FDA-approved drugs [on-label and/or off-label (N = 54) or with experimental drugs in clinical trials (additional five patients); University of California San Diego Molecular Tumor Board assessment]: 45, by OncoKB (http://oncokb.org/#/). The tissue and blood concordance rates for common specific alterations ranged from 62.3% to 86.9% (median = 5 months between tests). In serial samples from patients on anti-EGFR therapy, multiple emerging alterations in genes known to be involved in therapeutic resistance, including KRAS, NRAS, BRAF, EGFR, ERBB2, and MET were detected. In conclusion, over 80% of patients with stage IV colorectal cancer had detectable ctDNA, and the majority had potentially actionable alterations. Concordance between tissue and blood was between 62% and 87%, despite a median of 5 months between tests. Resistance alterations emerged on anti-EGFR therapy. Therefore, biopsy-free, noninvasive ctDNA analysis provides data relevant to the clinical setting. Importantly, sequential ctDNA analysis detects patterns of emerging resistance allowing for precision planning of future therapy.
Finding Waldo: The Evolving Paradigm of Circulating Tumor DNA (ctDNA)-Guided Minimal Residual Disease (MRD) Assessment in Colorectal Cancer (CRC). [2022]Circulating tumor DNA (ctDNA), the tumor-derived cell-free DNA fragments in the bloodstream carrying tumor-specific genetic and epigenetic alterations, represents an emerging novel tool for minimal residual disease (MRD) assessment in patients with resected colorectal cancer (CRC). For many decades, precise risk-stratification following curative-intent colorectal surgery has remained an enduring challenge. The current risk stratification strategy relies on clinicopathologic characteristics of the tumors that lacks precision and results in over-and undertreatment in a significant proportion of patients. Consequently, a biomarker that can reliably identify patients harboring MRD would be of critical importance in refining patient selection for adjuvant therapy. Several prospective cohort studies have provided compelling data suggesting that ctDNA could be a robust biomarker for MRD that outperforms all existing clinicopathologic criteria. Numerous clinical trials are currently underway to validate the ctDNA-guided MRD assessment and adjuvant treatment strategies. Once validated, the ctDNA technology will likely transform the adjuvant therapy paradigm of colorectal cancer, supporting ctDNA-guided treatment escalation and de-escalation. The current article presents a comprehensive overview of the published studies supporting the utility of ctDNA for MRD assessment in patients with CRC. We also discuss ongoing ctDNA-guided adjuvant clinical trials that will likely shape future adjuvant therapy strategies for patients with CRC.
Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study). [2018]Purpose: Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy.Experimental Design: This prospective study enrolled consecutive patients with mCRC receiving a first- or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C0), second (C1) and/or third (C2) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hypermethylation (WIF1, NPY). CT scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity, and treatment line.Results: Eighty-two patients with mCRC treated in first- (82.9%) or second- (17.1%) line chemotherapy were included. Patients with a high (>10 ng/mL) versus low (≤0.1 ng/mL) ctDNA concentration at C0 had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5-12.6; P < 0.0001). By analyzing the evolution of the ctDNA concentration between C0 and C2 or C1 (C2or1), we classified the patients in two groups (named "good" or "bad ctDNA responders"). In multivariate analysis, patients belonging to the group called "good ctDNA responder" (n = 58) versus "bad ctDNA responder" (n = 15) had a better objective response rate (P < 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40; P < 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11-0.57; P < 0.001).Conclusions: This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC. Clin Cancer Res; 23(18); 5416-25. ©2017 AACR.