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

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.

Inclusion criteria

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

• 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).
• 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.
• 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.
• 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).
• Current treatment with another investigational drug or participation in another investigational study.
• Patient unable to comply with the study protocol owing to psychological, social or geographical reasons.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
• Inadequate contraception (male or female patients) if of childbearing or procreational potential.
• Current clinically unresolved cardiovascular disease.
• Acute or subacute intestinal occlusion or history of inflammatory bowel disease.
• Pre-existing neuropathy > grade 1. Known grade 3 or 4 allergic reaction to any of the components of the treatment.
• Has a known DihydroPyrimidine Dehydrogenase (DPD) deficiency.
• Has a known Gilbert Syndrome or UGT1A1 homozygous *28/*28 germline variant.
• Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required.
• 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.
• Has a known history of active Bacillus Tuberculosis (TB).