Personalizing Chemotherapy Selection After Surgery for Patients With Stage III Colorectal Cancer Using a Blood Test

NCT07340567 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: UC-GIG-2410
• Study Type: interventional
• Target: 2,450
• Locations: 2 countries
• Sites: 5

Brief Summary

CIRCULATE-III is an international, multicenter, open-label, randomized phase III trial designed to use ctDNA as a selection criterion for intensification or de-escalation of adjuvant chemotherapy. Eligible patients are randomly assigned to the following treatment groups:

• Patients who test negative for ctDNA receive either capecitabine for 6 months (experimental group) or oxaliplatin + capecitabine for 3 months (standard group).
• Patients who test positive for ctDNA receive either FOLFIRINOX for 6 months (experimental group) or FOLFOX for 6 months (standard group). Patient participation in the trial will not exceed 66 months after randomization, including a maximum treatment duration of 6 months and a follow-up period of 60 months.

Conditions

Colorectal Cancer

Outcome Measures

Primary Outcomes (2)

• Non-inferiority of 6-month CAPE vs 3-month CAPOX ACT in terms of 3-year Disease Free Survival ctDNA-negative cohort

  ctDNA-negative cohort: The primary objective is to evaluate the non-inferiority of 6-month capecitabine alone (CAPE; de-escalation strategy) compared to 3-month capecitabine + oxaliplatin (CAPOX; standard therapy) in terms of 3-year disease-free survival (DFS) as adjuvant chemotherapy (ACT) protocol in stage III pMMR/MSS CRC patients with post-operative ctDNA-negative.

  DFS will be defined as time from date of randomization until the date of first documented recurrence local or metastatic, date of second colorectal cancer, or date of death from any cause wichever came first, assessed up to 42 months.

• Superiority of 6-month FOLFIRINOX vs 6-month FOLFOX ACT in terms of 3-year Disease Free Survival ctDNA-positive cohort

  ctDNA-positive cohort: The primary objective is to evaluate the superiority of 6-month FOLFIRINOX (escalation strategy) compared to 6-month FOLFOX (standard therapy) in terms of 3-year DFS as an ACT protocol in stage III pMMR/MSS CRC patients with post-operative ctDNA-positive.

  DFS will be defined as time from date of randomization until the date of first documented recurrence local or metastatic, date of second colorectal cancer, or date of death from any cause, wichever came first, assessed up to 42 months.

Study Arms (4)

ctDNA-negative cohort : Capecitabine alone

EXPERIMENTAL

ctDNA-negative patients will be included and randomized to de-escalation treatment (capecitabine \[CAPE\] for 6 months).

Drug: Capecitabine

ctDNA-negative cohort : Capecitabine + oxaliplatin

ACTIVE COMPARATOR

ctDNA-negative patients will be included and randomized to standard treatment (CAPOX for 3 months).

Drug: Capecitabine; Drug: Oxaliplatin

ctDNA-positive cohort : FOLFIRINOX

EXPERIMENTAL

ctDNA-positive patients will be randomized to escalation treatment (5FU + irinotecan + oxaliplatin \[FOLFIRINOX\] for 6 months).

Drug: Folfirinox

ctDNA-positive cohort : FOLFOX

ACTIVE COMPARATOR

ctDNA-positive patients will be randomized to standard treatment (FOLFOX for 6 months).

Drug: FOLFOX regimen

Interventions

Capecitabine DRUG

De-escalation treatment (capecitabine \[CAPE\] for 6 months). Or Standard treatment (CAPOX for 3 months)

ctDNA-negative cohort : Capecitabine + oxaliplatin; ctDNA-negative cohort : Capecitabine alone

Oxaliplatin DRUG

Standard treatment (CAPOX for 3 months)

ctDNA-negative cohort : Capecitabine + oxaliplatin

Folfirinox DRUG

Escalation treatment (5FU + irinotecan + oxaliplatin \[FOLFIRINOX\] for 6 months)

ctDNA-positive cohort : FOLFIRINOX

FOLFOX regimen DRUG

Standard treatment (FOLFOX for 6 months)

ctDNA-positive cohort : FOLFOX

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must have signed a written informed consent prior to any trial specific procedures. When the patient is physically unable to give their written consent, an impartial witness of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent
• Age ≥18 years and \<80 years (for patients aged \>70 years: G8 geriatric questionnaire score\>14)
• Histologically confirmed stage III pMMR/MSS colon and high rectum adenocarcinoma (T, N1 or N2, M0) excluding medium and low rectal cancers (≥12 cm from the anal verge by endoscopy and/or above the peritoneal reflection at surgery are still eligible), without gross or microscopic evidence of residual disease after surgery with curative intent.
• ECOG performance status 0-1 (fit to receive FOLFIRINOX therapy)
• No prior chemotherapy for CRC
• No prior abdominal or pelvic irradiation for CRC
• Adequate hematological function: neutrophils ≥1,500 /mm3, platelet count ≥100,000/mm3, hemoglobin ≥9 g/dL (5,6 mmol/L)
• Total bilirubin ≤1.5 x ULN (upper limit of normal)
• ASAT and ALAT ≤2.5 x ULN
• Alkaline phosphatase ≤2.5 x ULN
• Serum creatinine ≤120 μmol/L or creatinine clearance ≥50 mL/min according to Modification of Diet in Renal Disease (MDRD) formulae
• Tumor tissue available at baseline
• Women of childbearing potential must have negative serum pregnancy test done within 7 days before the start of study treatment
• Men and women of childbearing potential must agree to use adequate contraception methods for the duration of study treatment and for 6 months after treatment discontinuation
• Patients must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures

You may not qualify if:

• Peripheral neuropathy grade ≥1
• Patients who have received neo-adjuvant treatment.
• Comorbidity influencing the 3-year patients' survival including clinically relevant cardiovascular disease, such as Ischemic myocardial infarction in the last year and/or unstable ischemic cardiopathy
• Contra-indication to chemotherapy (inadequate bone marrow, hepatic, renal functions, hypersensitivity to one of the treatments or any of the excipients)
• Patient must not have received bone marrow transplant
• Participation in another therapeutic trial
• Partial or complete dihydropyrimidine deshydrogenase (DPD) deficiency.
• MSI/dMMR tumors
• Medical history of other concomitant or previous malignant disease, except adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, or cancer in complete remission for ≥ 5 years.
• Pregnant or breastfeeding women.
• Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial social or psychological reasons
• Persons deprived of their liberty or under protective custody or guardianship.

Sponsors & Collaborators

• UNICANCER: lead
• Natera, Inc.: collaborator

Study Sites (5)

Institut Gustave Roussy

Villejuif, 94800, France

Location

Sahlgrenska University Hospital

Gothenburg, 41345, Sweden

Location

Skäne University Hospital

Lund, 22185, Sweden

Location

Södersjukhuset

Stockholm, 11883, Sweden

Location

Onkologikliniken

Uppsala, 75185, Sweden

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Capecitabine; Oxaliplatin; folfirinox; Folfox protocol

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Coordination Complexes; Organic Chemicals

Central Study Contacts

Emilie BRUMENT, MsC

CONTACT

+33(0)171936164; e-brument@unicancer.fr

Léonor BENHAIM, MD

CONTACT

Leonor.BENHAIM@gustaveroussy.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 18, 2025
• First Posted: January 14, 2026
• Study Start: May 1, 2026
• Primary Completion (Estimated): November 1, 2032
• Study Completion (Estimated): November 1, 2035
• Last Updated: January 14, 2026

Record last verified: 2025-12

Locations

FR (1); SE (4)