The RESET C2 trial aims to introduce organ sparing treatment or watch-and-wait (WW) to patients with localized deficient mismatch repair (dMMR) colon cancer through use of neoadjuvant pembrolizumab. Patients will be divided into four treatment arms based on their surgical and oncologic risks. Each arm provides different intensity neoadjuvant immunotherapy regimens. Patients with complete response at disease restaging procedures will be offered non-operative management, whereas those with non-complete response will proceed to surgery ± adjuvant chemotherapy as standard of care. A WW protocol with regular disease surveillance continues over survivorship. If there is recurrence, surgery and/or appropriate oncologic therapy will be offered determined by multi-disciplinary teams. This is a national, non-randomised, investigator-initiated trial including patients from 13 hospitals across Denmark. The rationale, design, and clinical response metrics are derived from the RESET C study (NCT05662527) showing efficacy, safety and feasibility of neoadjuvant pembrolizumab in this cohort.
Age ≥ 18 years
Written informed consent
Clinical UICC stage I-III dMMR colon carcinoma
Indication for elective curative-intent surgery
Patients deemed to be non-surgical candidates by MDT
Patients with a need for emergent surgery due to tumour obstruction
Contraindications to pembrolizumab, including allergy and hypersensitivity reactions, assessed by the study investigator(s)
Any serious or uncontrolled medical disorder, including other malignant disease, that may increase the risk associated with participation or drug administration.
Parallel
1 Cycle of Pembrolizumab
Drug1 cycle of 4mg/kg (maximum of 400mg) every 6 weeks
2 Cycles of Pembrolizumab
Drug2 Cycles of Pembrolizumab 4mg/kg (maximum of 400mg) every 6 weeks
3 Cycles of Pembrolizumab
Drug3 Cycles of Pembrolizumab 4mg/kg (maximum of 400mg) every 6 weeks
Additional Cycle of Pembrolizumab
DrugAn additional 4mg/kg (maximum of 400mg) cycle of pembrolizumab in the case of non-complete response
Proportion of patients with clinical complete response (cCR)
The proportion of patients achieving a clinical complete response defined as 1) the absence of residual local tumour based on predefined endoscopic criteria and 2) absence of metastatic disease on cross-sectional CT imaging. Pathological examination may be performed to support the local tumour response assessment when endoscopic findings are equivocal. These tissue specimens will be reported as per the Mandard Tumour Regression Grading system with pathologic Complete Response (pCR) defined as Mandard Tumour Regression Grade 1.
Overall Survival (OS)
Time from inclusion to death from any cause
Disease-free survival (DFS)
Time from inclusion to disease recurrence or death from any cause, whichever occurs first.
Major patholological response (MPR) in patients undergoing surgery as per Mandard TRG
Proportion of patients with no residual tumour cells (Mandard Tumour Regression Grade 1) or rare residual tumour cells (Mandard Tumour Regression Grade 2) in the histopathological section after surgery.
Adverse events related to pembrolizumab as per Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Adverse events related to pembrolizumab, assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The scale of adverse events ranges from a minimal value of 1 (mild) to a maximum value of 5 (death) with higher values representing worse outcomes.
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Ismail Gögenur
Lead sponsor
Zealand University Hospital
Sponsor institution
Rigshospitalet, Denmark
Collaborator
Bispebjerg Hospital
Collaborator
Herlev and Gentofte Hospital
Collaborator
Gødstrup Hospital
Collaborator
Horsens Hospital
Collaborator
Hvidovre University Hospital
Collaborator
Odense University Hospital
Collaborator
Randers Regional Hospital
Collaborator
Slagelse Hospital
Collaborator
Vejle Hospital
Collaborator
Aalborg University Hospital
Collaborator
Aarhus University Hospital
Collaborator
Zealand University Hospital
Collaborator
University of Copenhagen
Collaborator
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