Colon Cancer Stage II
Conditions
Keywords
circulating tumour DNA, ctDNA, adjuvant chemotherapy
Brief summary
The CIRCULATE study evaluates the adjuvant therapy in patients with colon cancer UICC stage II. The primary aim of the study is to compare the disease free survival in patients who are positive for postoperative circulating tumour DNA with vs. without capecitabine.
Detailed description
CIRCULATE is an investigator-initiated, multicentre, prospective, randomised, controlled trial. Screening phase: Patients with colon cancer (or rectal cancer, if a radiation is not indicated i.e. due to the tumour localisation) are postoperatively screened for this trial. For this purpose, they sign an informed consent for screening. The formalin fixed paraffin embedded (FFPE) tumour block is shipped to one of the central pathological laboratories and is analysed for microsatellite instability and by panel analysis for frequent mutations in the colorectal cancer. A plasma sample is sent in parallel to the central laboratory for ctDNA. The screening is preferably performed before the patient is discharged from the surgical department and at the latest 5 weeks after resection to allow sufficient time for the analysis. The patient- specific tumour mutations known from the panel analysis are measure in the patients plasma by ultra deep sequencing. The results of the analysis - positive for circulating tumour DNA (ctDNApos) or negative for circulating tumour DNA (ctDNAneg) - is not communicated to the patient or the investigator. Randomised phase: Four to eight weeks after resection, the patient presents at an investigator that is experienced with chemotherapy (i.e. Medical Oncologist) and consent for the randomised part of the study with a second informed consent form. If this baseline visit confirms that there are not contraindications to chemotherapy and if no other exclusion criteria exist, the patient is randomised: * ctDNApos patients are randomised (2:1) in chemotherapy (with capecitabine) or follow-up, * ctDNAneg patients are randomised (1:4) in follow-up or off study which means that the follow-up will be organised within the routine clinical practice. The result of the ctDNA will not be communicated to the patients and investigators, so that patients in the arm follow-up remain blinded to the ctDNA result. Due to the randomisation ratio, the prognosis of these patients is similar to those in stage II without any ctDNA analysis and differs only slightly from patients not enrolled into a clinical trial. Patients in the arm chemotherapy receive adjuvant therapy with 6 months capecitabine. The investigator can decide to add oxaliplatin and to shorten the adjuvant chemotherapy to 3 months if oxaliplatin is added. Patients in the arms chemotherapy and follow-up are followed with the same methods and time point within the study. Patients in the arm off study are recommended to be follow up according to the guidelines for stage II in the routine practice.
Interventions
DRUGCapecitabine
6 months capecitabine, in combination with oxaliplatin 3 to 6 months capecitabine
Sponsors
Technische Universität Dresden
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for screening phase: 1. Resected colon cancer stage II, OR Resected rectal cancer stage II, if there was no indication for radiotherapy (i.e. due to the localisation in the upper third of the rectum ), so that the treatment follows the recommendations for colon cancer. Patients, in whom the tumour stage is not yet know, can be enrolled into the screening. 2. Signed informed consent for the screening Phase Inclusion criteria for the randomised phase: 1. Resected colon cancer stage II, OR resected rectal cancer stage II, if there was no indication for radiotherapy (i.e. due to the localisation in the upper third of the rectum), so that the treatment follows the recommendations for colon cancer. 2. Known microsatellite or mismatch repair status 3. Confirmation, that the ctDNA result is available 4. Signed second informed consent (for the randomised phase)
Exclusion criteria
for Screening: 1. Patients with known microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) 2. Known clinical high risk situation if it is regarded as certain indication for an adjuvant chemotherapy 3. Patients, who have an obvious contra-indication for adjuvant chemotherapy (i.e. due to the performance status, comorbidity, active second cancer or age). It should be considered that patients with an age of more than 75 years frequently not fulfil criteria for adjuvant chemotherapy. 4. R1- or R2-status (patients with \[still\] unknown R-status can be screened) 5. Patients, in whom the randomisation or chemotherapy is unfeasible due to logistic reasons (travel distance, compliance) 6. Age \< 18 years 7. Pregnant or breast feeding patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease free Survival (DFS) | for the primary endpoint after 154 events (approx. 60 months after study start) | Disease free survival of ctDNA positive patients randomised to chemotherapy vs. follow-up, measured from randomisation to any recurrence, metastasis, second colorectal or non colorectal cancer and death from any cause. The primary endpoint will be tested in all randomised ctDNA positive patients and be evaluated by a stratified log rank test. Interims analysis after 93 events (approx. 38 months after study start), final analysis for the primary endpoint after 154 events (approx. 60 months after study start). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease free survival in ctDNAneg patients randomised to follow up | 3 years | Disease free survival in ctDNAneg patients randomised to follow up (rate of patients disease free and alive 3 years after randomisation according to Kaplan-Meier estimation with 95% CI, intention-to-treat analysis). Any recurrence, metastasis, second colorectal or non-colorectal cancer and death from any cause is regarded as event (rate of patients disease free and alive 3 years after randomisation according to Kaplan-Meier estimation with 95% CI, intention-to-treat analysis). Any recurrence, metastasis, second colorectal or non- colorectal cancer and death from any cause is regarded as event |
| Overall survival in ctDNAneg patients randomised to follow up | 5 years | Overall survival in ctDNAneg patients randomised to follow up (rate of patients alive after 5 years after randomisation according to Kaplan-Meier estimation with 95% CI) |
| Overall survival in ctDNApos patients with adjuvant therapy vs follow-up | 5 years | Overall survival in ctDNApos patients with adjuvant therapy vs follow-up, measured from randomisation to death from any cause, in all randomised ctDNA positive patients and be evaluated by a stratified log rank test. |
| Site of metastases | 5 years | Site of metastases (lymph node vs. peritoneal/local recurrence vs other) in ctDNApos vs. ctDNAneg patients who have a recurrence / metastases |
| Frequency of adverse events from start of chemotherapy until 30 days after chemotherapy | 5 years | Frequency of adverse events from start of chemotherapy until 30 days after chemotherapy (descriptive analysis for patients randomised to chemotherapy who have received at least one dose of chemotherapy). |
| Disease free and overall survival of ctDNApos vs. ctDNAneg patients randomized to follow-up | 3 years and 5 years | Disease free and overall survival of ctDNApos vs. ctDNAneg patients randomized to follow-up (measured from randomisation to the event in an intention-to-treat analysis by stratified log rank test). Any recurrence, metastasis, second colorectal or non-colorectal cancer and death from any cause are regarded as event for DFS. Death of any cause will be regarded as event for overall survival. |
Countries
Germany
Contacts
Primary ContactGunnar Folprecht, Prof.
Outcome results
None listed