Circulating Tumour DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II Evaluation (CIRCULATE)
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|ClinicalTrials.gov Identifier: NCT04089631|
Recruitment Status : Not yet recruiting
First Posted : September 13, 2019
Last Update Posted : September 13, 2019
|Condition or disease||Intervention/treatment||Phase|
|Colon Cancer Stage II||Drug: Capecitabine||Phase 3|
CIRCULATE is an investigator-initiated, multicentre, prospective, randomised, controlled trial.
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.
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||4812 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Circulating Tumour DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II Evaluation (CIRCULATE) AIO-KRK-0217|
|Estimated Study Start Date :||October 2019|
|Estimated Primary Completion Date :||November 2022|
|Estimated Study Completion Date :||July 2026|
Capecitabine mono or Capecitabine/Oxaliplatin as investigator choice:
Patients who are positive for postoperative ctDNA (ctDNApos) and not microsatellite instable are randomized (2:1) to adjuvant chemotherapy with capecitabine or to follow up.
Capecitabine 2 x 1250 mg/m^2, oral (d1-14), repeated at day 22 (- 2 ... + 6 days). Patients with a GFR between 30 and 50 ml/min start with capecitabine dose of 2 x 1000 mg/m^2. Treatment duration: 8 cycles (approx. 6 months)
Capecitabine, if combined with Oxaliplatin (investigator choice):
If the investigation decides to add oxaliplatin, the following schedule should be used:
[Oxaliplatin 130 mg/m^2 i.v. (2 hours on d1)] Capecitabine 2 x 1000 mg/m^2, oral (d1-14), repeated at day 22 (- 2 ... + 6 days) Treatment duration: 4 or 8 cycles (approx. 3 or 6 months)
6 months capecitabine, in combination with oxaliplatin 3 to 6 months capecitabine
Other Name: Xeloda
No Intervention: Follow-up
Patients negative for postoperative ctDNA (ctDNAneg) are randomized (1:4) to follow-up within CIRCULATE or to routine follow up outside the Trial protocol.
- Disease free Survival (DFS) [ Time Frame: 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).
- Overall survival in ctDNApos patients with adjuvant therapy vs follow-up [ Time Frame: 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.
- Disease free survival in ctDNAneg patients randomised to follow up [ Time Frame: 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" [ Time Frame: 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)
- Disease free and overall survival of ctDNApos vs. ctDNAneg patients randomized to "follow-up" [ Time Frame: 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.
- Site of metastases [ Time Frame: 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 [ Time Frame: 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).
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04089631
|Contact: Gunnar Folprecht, Prof.||+49 351 458 4794||Gunnar.Folprecht@uniklinikum-dresden.de|
|Principal Investigator:||Gunnar Folprecht, Prof.||University hospital "Carl Gustav Carus" Dresden|