Circulating Tumour DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II Evaluation

NCT ID: NCT04089631

Last Updated: 2020-08-06

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 4812 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-06-26
• Study Completion Date: 2026-06-30

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.

Conditions

Colon Cancer Stage II

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Chemotherapy

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)

Group Type: EXPERIMENTAL

Capecitabine

Intervention Type: DRUG

6 months capecitabine, in combination with oxaliplatin 3 to 6 months capecitabine

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Capecitabine

6 months capecitabine, in combination with oxaliplatin 3 to 6 months capecitabine

Intervention Type: DRUG

Other Intervention Names

Xeloda

Eligibility Criteria

Inclusion Criteria

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

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

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

1. Patients with 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. R1- or R2- status, or unknown R- status (Rx)

4. Number of investigated lymph nodes < 10

5. WHO performance status ≥ 2

6. Colon or rectal cancer with UICC stage III or IV

7. Second cancer, except

1. simultaneous or metachronous colon or rectal cancer with UICC stage ≤ I,

2. curatively treated basal cell carcinoma or squamous cell carcinoma of the skin and in-situ cervical carcinoma

3. tumours with a disease free survival of more than five years

8. Contra indications for chemotherapy, especially:

1. Leukocytes < 3,0 Gpt/l

2. Neutrophil granulocytes < 1,5 Gpt/l

3. Thrombocytes < 100 Gpt/l

4. alanine aminotransferase (ALAT) or (aspartate aminotransferase) ASAT > 3x ULN

5. Creatinine clearance (calculated according Cockcroft-Gault) < 30 ml/min

9. Comorbidities relevantly interfering with the prognosis of the patients, i.e.:

1. heart insufficiency NYHA III/IV

2. relevant coronary heart disease,

3. Diabetes mellitus with late sequelae

10. Organ, stem cell or bone marrow transplantation

11. Known hypersensitivity to capecitabine In case of known hypersensitivity to oxaliplatin, the patients can participate, but not receive oxaliplatin

12. Medication with brivudine, sorivudine or analogues in the last four weeks before planned treatment start

13. Known dihydropyrimidine dehydrogenase (DPD)-deficiency

14. Acute infections

15. Known HIV- infections, known active hepatitis B or C-infection

16. Participation at another interventional study for medical treatment during the last four weeks before randomisation

17. Neoadjuvant therapy before resection

18. Patients, in whom the randomisation or chemotherapy is unfeasible due to logistic reasons (travel distance, compliance)

19. Age < 18 years

20. Pregnant or breast feeding patients

21. Women of childbearing potential and men with partner with childbearing potential who are not willing to take appropriate precautions to avoid pregnancy with a highly effective method in case they are randomised to "chemotherapy"

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Technische Universität Dresden

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gunnar Folprecht, Prof.

Role: PRINCIPAL_INVESTIGATOR

University hospital "Carl Gustav Carus" Dresden

Locations

Universitaetsklinikum Carl Gustav Carus, Medizinische Klinik

Dresden, Saxony, Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Gunnar Folprecht, Prof.

Role: CONTACT

Gunnar.Folprecht@uniklinikum-dresden.de

+49 351 458 4794

Facility Contacts

Gunnar Folprecht, Dr.

Role: primary

gunnar.folprecht@uniklinikum-dresden.de

+49 351 458 4794

Other Identifiers

2018-003691-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

01KG1817

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

AIO-KRK-0217

Identifier Type: OTHER

Identifier Source: secondary_id

TUD-CIRC01-071

Identifier Type: -

Identifier Source: org_study_id