Circulating Tumor Cell, Colorectal Neoplasms Malignant, Minimal Residual Disease
Conditions
Brief summary
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.
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.
Interventions
DRUGFOLFOXIRI
Patients will receive 12 cycles each 14 days
DRUGCAPOX
Patients will receive 8 cycles each 21 days
Sponsors
Fundación para la Investigación del Hospital Clínico de Valencia
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single to double arm transition study in which patients are firstly enrolled into a single arm (Phase IIa) study expandable to a randomized double arm (Phase IIb). In the first stage (Phase IIa) the success of the experimental treatment (FOLFOXIRI) is compared to a fixed value. If the pre-fixed result is achieved, the trial will be expanded to a phase IIb in which patients will be enrolled to randomly receive experimental treatment (FOLFOXIRI) or control (CAPOX).
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with ctDNA clearance following FOLFOXIRI treatment | Prior to treatment initiation, immediately after adjuvant chemotherapy completion, and every 4 months for 2 years (phase IIa). | Proportion of patients with detectable circulating tumor DNA (ctDNA) prior to treatment who become ctDNA-negative following intensive adjuvant treatment with FOLFOXIRI. |
| Difference in ctDNA clearance rate between FOLFOXIRI and CAPOX(FOLFOXIRI) versus conventional adjuvant therapy (CAPOX). | Prior to treatment initiation, immediately after adjuvant chemotherapy completion, and every 4 months for 2 years (phase IIb). | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free survival in patients with positive ctDNA | At 24 months after the end of treatment (phase IIb). | Disease-free survival in patients with positive circulating tumor DNA (ctDNA), compared between the FOLFOXIRI and CAPOX treatment groups. |
| Disease-free survival according to ctDNA clearance status | At 12 months after the end of treatment (phase IIb). | 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. |
| Treatment-related toxicity of FOLFOXIRI compared with CAPOX | During the treatment period and immediately after adjuvant chemotherapy completion (phase IIb). | Incidence and severity of treatment-related adverse events during adjuvant chemotherapy, compared between patients treated with FOLFOXIRI and those treated with CAPOX. |
| Quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) | At baseline, 3 months after treatment initiation, and immediately after adjuvant chemotherapy completion (phase IIb). | 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. |
| Quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) | At baseline, 3 months after treatment initiation, and immediately after adjuvant chemotherapy completion (phase IIb). | 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. |
Countries
Spain
Contacts
PRINCIPAL_INVESTIGATORAndrés Cervantes Ruipérez, MD
Hospital Clínico Universitario de Valencia
Outcome results
None listed