Circulating Tumor DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II-III

Phase II Randomized Trial to Assess the Effect of Intensive vs Standard Adjuvant Chemotherapy in Localized Colon Cancer With Circulating Tumor DNA

This trial has been designed to prove the feasibility of using liquid biopsy detection of minimal residual disease (MRD) to guide the postsurgical clinical management of early colon cancer patients. Moreover, it is important to define if conventional (CAPOX) versus intensive (FOLFOXIRI) adjuvant chemotherapy could convert plasma ctDNA positive into a ctDNA negative status.

Study Overview

• Status: Active, not recruiting
• Conditions: Minimal Residual Disease; Circulating Tumor Cell; Colorectal Neoplasms Malignant
• Intervention / Treatment: Drug: FOLFOXIRI; Drug: CAPOX

Detailed Description

The detection of circulating tumor DNA immediately after surgery with curative-intent identifies minimal residual disease and has been demonstrated as a surrogate of disease-free survival. This finding could guide adjuvant postoperative treatment in early colon cancer patients.

The efficacy and safety of FOLFOXIRI were previously tested in metastatic colorectal cancer patients. The Investigators hypothesize that an intensive adjuvant chemotherapy with FOLFOXIRI regimen could convert patients with detectable ctDNA into ctDNA negative indicating appropriate control of minimal residual disease. Moreover, FOLFOXIRI could have a higher conversion rate than conventional CAPOX therapy.

The current trial proposes a two-step approach. In the first part, a maximum of 40 patients with positive plasma ctDNA will be receiving an intensive adjuvant treatment with FOLFOXIRI, which is considered at the moment standard of care for metastatic patients. This part will be taken as a go/no go decision. The aim is to get at least 14 patients with ctDNA negative after such adjuvant treatment. If these figures are not met, the trial will be stopped due to futility, recognizing that such adjuvant treatment cannot control MRD. On the other hand, if these numbers are reached, a second part is designed as an exploratory phase II study to further randomize 124 patients with ctDNA positive into CAPOX versus FOLFOXIRI for six months, assessing again ctDNA conversion into a negative status. The aim of this part is to estimate differences in converting plasma ctDNA into negative among the conventional versus intensive adjuvant treatment.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08003
    • Hospital Del Mar
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Córdoba, Spain, 14004
    • Hospital Universitario Reina Sofia
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Valencia, Spain, 46014
    • Hospital General Universitario de Valencia
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Hospital Universitario de Bellvitge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. CIRCULATE-SPAIN-01 trial written informed consent.
2. Age ≥ 18 years and ≤ 75 years.
3. Histologically confirmed diagnosis of operable stage II or stage III Colon Cancer.
4. Postoperative, ctDNA positive.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

6. Normal organ functions, as follows:

   • Absolute neutrophil count (ANC) ≥ 1500/μL.
   • Platelets ≥ 100.000/μL.
   • Hemoglobin ≥ 9.0 g/dL OR ≥ 5.6 mmol/L.
   • Total bilirubin ≤ 1.5 x upper level of normality (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 x ULN.
   • Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤ 2.5 x ULN.

Note: Synchronous primary tumours are accepted. Note: Patients with rectal cancer above the peritoneal reflection, who have not undergone postoperative chemotherapy or radiotherapy and who have risk factors, may be included in the trial.

Exclusion Criteria:

1. Patients having a MicroSatellite Instability High (MSI-H) or MisMatch Repair Deficient (MMRd) tumor are excluded from the study (done according to standard clinical practice).
2. History of another neoplastic disease, unless in remission for ≥ 5 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
3. Had an incomplete diagnostic colonoscopy and/or polyps' removal for patients in whom the remaining colon was not removed or explored. Note: Patients with intraoperative complete colonoscopy or early perioperative complete colonoscopy and/or patients with incomplete colonoscopy, but who do have a CT Colono or Intraoperative Colonoscopy, may be eligible to be recruited in the study.
4. Macroscopic or microscopic evidence of residual tumor (R1 or R2 resections). Patients should never have had any evidence of metastatic disease (including presence of tumor cells in the peritoneal lavage).
5. Current treatment with another investigational drug or participation in another investigational study.
6. Patient unable to comply with the study protocol owing to psychological, social or geographical reasons.
7. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
8. Inadequate contraception (male or female patients) if of childbearing or procreational potential.
9. Current clinically unresolved cardiovascular disease.
10. Acute or subacute intestinal occlusion or history of inflammatory bowel disease.
11. Pre-existing neuropathy > grade 1. Known grade 3 or 4 allergic reaction to any of the components of the treatment.
12. Has a known DihydroPyrimidine Dehydrogenase (DPD) deficiency.
13. Has a known Gilbert Syndrome or UGT1A1 homozygous *28/*28 germline variant.
14. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required.
15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus infection. Note: no testing for Hepatitis B and Hepatitis C is required.
16. Has a known history of active Bacillus Tuberculosis (TB).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FOLFOXIRI; FOLFOXIRI intensive adjuvant chemotherapy	Drug: FOLFOXIRI; Patients will receive 12 cycles each 14 days; Other Names: intensive adjuvant chemotherapy
Active Comparator: CAPOX; CAPOX standard adjuvant chemotherapy	Drug: CAPOX; Patients will receive 8 cycles each 21 days; Other Names: standard adjuvant chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with ctDNA clearance following FOLFOXIRI treatment	Proportion of patients with detectable circulating tumor DNA (ctDNA) prior to treatment who become ctDNA-negative following intensive adjuvant treatment with FOLFOXIRI.	Prior to treatment initiation, immediately after adjuvant chemotherapy completion, and every 4 months for 2 years (phase IIa).
Difference in ctDNA clearance rate between FOLFOXIRI and CAPOX(FOLFOXIRI) versus conventional adjuvant therapy (CAPOX).	Proportion of patients with detectable circulating tumor DNA (ctDNA) prior to treatment who become ctDNA-negative following adjuvant chemotherapy, compared between the intensive treatment group (FOLFOXIRI) and the standard-of-care group (CAPOX).	Prior to treatment initiation, immediately after adjuvant chemotherapy completion, and every 4 months for 2 years (phase IIb).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free survival in patients with positive ctDNA	Disease-free survival in patients with positive circulating tumor DNA (ctDNA), compared between the FOLFOXIRI and CAPOX treatment groups.	At 24 months after the end of treatment (phase IIb).
Disease-free survival according to ctDNA clearance status	Disease-free survival according to ctDNA clearance status (patients with positive ctDNA who become ctDNA-negative versus patients who remain ctDNA-positive), evaluated in each treatment arm.	At 12 months after the end of treatment (phase IIb).
Treatment-related toxicity of FOLFOXIRI compared with CAPOX	Incidence and severity of treatment-related adverse events during adjuvant chemotherapy, compared between patients treated with FOLFOXIRI and those treated with CAPOX.	During the treatment period and immediately after adjuvant chemotherapy completion (phase IIb).
Quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)	Quality of life will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), comparing scores between the FOLFOXIRI and CAPOX treatment groups. All scales and single-item measures are transformed to scores ranging from 0 to 100. Higher scores on functional scales represent a higher/healthier level of functioning, and a higher score on the global health status/quality of life scale represents better quality of life. Higher scores on symptom scales or symptom items represent a higher level of symptoms or problems and therefore a worse outcome.	At baseline, 3 months after treatment initiation, and immediately after adjuvant chemotherapy completion (phase IIb).
Quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29)	Colorectal cancer-specific quality of life, functioning, and symptoms will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29), comparing scores between the FOLFOXIRI and CAPOX treatment groups. All scales and single-item measures are transformed to scores ranging from 0 to 100. Higher scores on functional scales represent a higher/healthier level of functioning, whereas higher scores on symptom scales or symptom items represent a higher level of symptoms or problems and therefore a worse outcome.	At baseline, 3 months after treatment initiation, and immediately after adjuvant chemotherapy completion (phase IIb).

Collaborators and Investigators

• Sponsor: Fundación para la Investigación del Hospital Clínico de Valencia
• Investigators: Principal Investigator: Andrés Cervantes Ruipérez, MD, Hospital Clínico Universitario de Valencia

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: July 23, 2021
• First Submitted That Met QC Criteria: September 9, 2026
• First Posted (Actual): September 15, 2026

Study Record Updates

• Last Update Posted (Actual): September 15, 2026
• Last Update Submitted That Met QC Criteria: September 9, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Colonic Diseases; Neoplastic Processes; Neoplasm Metastasis; Pathological Conditions, Signs and Symptoms; Neoplasm, Residual; Colonic Neoplasms; Neoplastic Cells, Circulating; FOLFOXIRI protocol
• Other Study ID Numbers: CIRCULATE-SPAIN-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No