Neoadjuvant Immunotherapy and Organ-sparing Treatment in Patients With Stage I-III dMMR Colon Cancer (RESET C2)

Neoadjuvant Immunotherapy and Organ-sparing Treatment in Patients With Stage I-III dMMR Colon Cancer: A National, Multicentre, Personalised, Phase II Study (RESET C2)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Immunotherapy; Pembrolizumab; DMMR Colorectal Cancer; Colon Cancer Stage I; Colon Cancer Stage II/III
• Intervention / Treatment: Drug: 1 Cycle of Pembrolizumab; Drug: Additional Cycle of Pembrolizumab; Drug: 2 Cycles of Pembrolizumab; Drug: 3 Cycles of Pembrolizumab

Detailed Description

Organ preservation in colorectal cancer has been pioneered in rectal cancer populations, where watch-and-wait (WW) strategies emerged from total neoadjuvant therapy. RESET C2 aims to brings this same treatment paradigm to colon cancer (CC). Despite improvements in surgical outcomes for CC over time, the risk of relapse and disproportionate complications in frail patients remain core challenges. Avoidance of surgery to limit these risks is attractive from a safety perspective but WW approaches have not been validated as curative and oncologically safe in a CC population. The subgroup of patients with CC and deficient mismatch repair (dMMR) proteins are ideal candidates for investigation as they demonstrate marked sensitivity to immunotherapy, which has the capacity to induce complete responses in a substantial proportion. The question of how this can be best leveraged for maximum benefit in a real-world setting remains to be answered.

In this study, 152 eligible participants will be recruited nationwide across 13 participating sites in Denmark. Following enrolment, clinicians will assign a surgical risk category using a composite of the American society of anaesthesiology (ASA) score and Eastern Cooperative Oncology Group performance status (ECOG). This input is combined with cancer stage data to allocate patients to one of four treatment arms. Depending on allocation, participants will receive between one to three consecutive cycles of up-front 4mg/kg pembrolizumab (max. 400mg) every six weeks. This is followed by a disease re-evaluation step, involving colonoscopy and contrast CT imaging. Colonoscopy is used to determine local disease response, and cross-sectional CT is used to confirm absence of distant disease. Participants with clinical complete response (cCR) will be eligible for WW, and those with non-cCR will be offered additional pembrolizumab before a second/final re-evaluation. Any patients with cCR at the final re-evaluation will be eligible for WW and those with non-cCR will be offered surgery. Quality of life (QoL) and late effects will be captured via patient reported outcome measures (PROMs) which will be distributed after enrolment, during immunotherapy, and at designated timepoints across survivorship. A separate cohort of 250 CC patients who undergo surgery without neoadjuvant treatment will complete identical PROMs and act as a comparator group after surgical treatment. Final analysis will compare QoL and late effects in patients who are allocated to WW (cCR), with those who receive neoadjuvant treatment and proceed to surgery (non-cCR), and finally those who proceed directly to surgery (matched cohort).

Across all treatment arms, enrolled patients will be offered multi-disciplinary prehabilitation. These functional, exercise, and nutrition interventions are graded in intensity and dependent on patient frailty and disease-factors. This forms the backbone of standard-of-care nationally for colorectal cancer patients and is implemented across all participating sites.

• Study Type: Interventional
• Enrollment (Estimated): 152
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ismail Gögenur, Professor; Phone Number: +4526336426; Email: igo@regionsjaelland.dk

Study Locations

• Denmark
  • Køge, Denmark, 4600
    • Zealand University Hospital
    • Contact: Ismail Gögenur Professor; Phone Number: +4526336426; Email: igo@regionsjaelland.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. Written informed consent
3. Clinical UICC stage I-III dMMR colon carcinoma
4. Indication for elective curative-intent surgery
5. ECOG status 0-2

Exclusion Criteria:

1. Patients deemed to be non-surgical candidates by MDT
2. Patients with a need for emergent surgery due to tumour obstruction
3. Contraindications to pembrolizumab, including allergy and hypersensitivity reactions, assessed by the study investigator(s)
4. Any serious or uncontrolled medical disorder, including other malignant disease, that may increase the risk associated with participation or drug administration.
5. Patients with colonic stents

Additional Circumstances:

In the following circumstances, eligibility will be individually verified:

• Synchronous colonic tumours (may be included if other lesions are biopsy-verified with dMMR status)
• Concurrent tumours (e.g., patients with prostate cancer may be included if this does not hinder their other cancer treatment or assessments of efficacy)

In the following circumstance patients may be excluded from the PROMs outcomes:

• Danish language skills insufficient to answer PROMs
• Unable to use eBoks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low and medium surgical risk participants with stage I-II CRC; These participants receive 1 cycle of up-front pembrolizumab before disease re-assessment. An additional cycle may given in the case of non-complete response	Drug: 1 Cycle of Pembrolizumab; 1 cycle of 4mg/kg (maximum of 400mg) every 6 weeks; Other Names: Keytruda; Drug: Additional Cycle of Pembrolizumab; An additional 4mg/kg (maximum of 400mg) cycle of pembrolizumab in the case of non-complete response
Experimental: Low and medium surgical risk participants with stage III CRC; These participants receive 2 cycles of up-front pembrolizumab before disease re-assessment (no additional cycles are offered if non-complete response)	Drug: 2 Cycles of Pembrolizumab; 2 Cycles of Pembrolizumab 4mg/kg (maximum of 400mg) every 6 weeks; Other Names: Keytruda
Active Comparator: High surgical risk participants with stage I-II CRC; These participants receive 2 cycles of up-front pembrolizumab before disease re-assessment. An additional cycle may given in the case of non-complete response	Drug: Additional Cycle of Pembrolizumab; An additional 4mg/kg (maximum of 400mg) cycle of pembrolizumab in the case of non-complete response; Drug: 2 Cycles of Pembrolizumab; 2 Cycles of Pembrolizumab 4mg/kg (maximum of 400mg) every 6 weeks; Other Names: Keytruda
Active Comparator: High surgical risk participants with stage III CRC; These participants receive 3 cycles of up-front pembrolizumab before disease re-assessment. An additional cycle may given in the case of non-complete response	Drug: Additional Cycle of Pembrolizumab; An additional 4mg/kg (maximum of 400mg) cycle of pembrolizumab in the case of non-complete response; Drug: 3 Cycles of Pembrolizumab; 3 Cycles of Pembrolizumab 4mg/kg (maximum of 400mg) every 6 weeks; Other Names: Keytruda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Periprocedural

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Time from inclusion to death from any cause	Up to 3 years
Disease-free survival (DFS)	Time from inclusion to disease recurrence or death from any cause, whichever occurs first.	Up to 3 years
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.	Perioperative
Planned or unplanned use of hospital services	Number and type of hospital encounters, including inpatient admissions, intensive care admissions, and outpatient visits, occurring in patients managed with watch-and-wait compared to those undergoing surgery. All hospital services will be recorded and analyzed to compare utilization between management strategies.	Up to 12 weeks
Change in physical fitness as measured by the 6-minute walk test	Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in the 6-Minute Walk Test (6MWT)	Up to 12 weeks
Change in physical fitness as measured by the sit-to-stand test	Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in the Sit-to-Stand Test	Up to 12 weeks
Change in physical fitness as measured by hand grip strength	Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in hand grip strength	Up to 12 weeks
Compliance with supervised training program	Assessment of compliance with supervised training measured as the number of supervised training sessions attended during the intervention period	Up to 12 weeks
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.	1 year
Adverse events related to surgery as per Clavien-Dindo (CD) classification	Surgical complications graded according to the Clavien-Dindo (CD) classification system. The scale of complications ranges from a minimal value of 0 (no complications) to a maximum value of 5 (death) with higher values representing worse outcomes.	Up to 12 weeks
Adverse events related to endoscopy as per American Society for Gastrointestinal Endoscopy (ASGE) lexicon	Endoscopic complications described according to the American Society for Gastrointestinal Endoscopy (ASGE) Lexicon for adverse events. This requires categorical reporting of timing (pre-procedure, intra-procedure, post-procedure <14 days, late >14 days), attribution to procedure (definite, probable, possible, unlikely) and severity grade (mild, moderate, severe, fatal).	Periprocedural
Change in global health status as measured by EORTC QLQ-C30	The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 100. Higher values indicate better outcomes for global health status and functional scales, lower values indicate better outcomes for symptom scales	Up to 5 years
Change in CRC-related quality of life as measured by EORTC QLQ-CR29	The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire for Colorectal Cancer (EORTC QLQ-CR29) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 100. Higher values indicate better outcomes for functional scales, lower values indicate better outcomes for symptom scales.	Up to 5 years
Change in bowel function as measured by CCBDS	The Colon Cancer Bowel Dysfunction Score (CCBDS) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 36. Lower values indicate better bowel function and less bowel dysfunction.	Up to 5 years
Change in overall daily function and care needs as measured by EQ-5D-5L	The EuroQol-5 Dimension 5 Levels (EQ-5D-5L) score is a patient reported outcome measure with the following characteristics: Minimum value: Less than 0. Maximum value: 1. Higher values indicate better health-related quality of life.	Up to 5 years
Change in fatigue as measured by FACIT-Fatigue	The Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 52. Higher values indicate less fatigue and better outcomes.	Up to 5 years
Change in fear of cancer recurrence as measured by FCRI-SF	The Fear of Cancer Recurrence Inventory - Short Form (FCRI-SF) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 36. Lower values indicate less fear of cancer recurrence.	Up to 5 years
Change in post-operative recovery as measured by QoR-15	The Quality of Recovery 15 (QoR-15) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 150. Higher values indicate better postoperative recovery.	Up to 5 years
Change in physical activity as measured by NPAQ-Short	The Nordic Physical Activity Questionnaire Short Form (NPAQ-Short) is a patient reported outcome measure with two close-ended question items and categorical responses paired with two ad-hoc items. These assess self-reported hours spent on physical activity in a typical week as well as historic trends and interest in being more physically active.	Up to 5 years
Change in physical fitness as measured by the Borg Rating of Perceived Exertion scale	Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in the Borg Rating of Perceived Exertion scale. Minimum value: 6. Maximal value: 20. Higher values indicate greater perceived effort and exercise intensity.	Up to 12 weeks
Change in frailty as measured by the G8 frailty score	Assessment of the change in frailty after supervised exercise training, evaluated by changes in the G8 frailty score. Minimum value: 0. Maximum value: 17. Higher values indicate better outcomes for functional impairment.	Up to 12 weeks

Collaborators and Investigators

• Sponsor: Ismail Gögenur
• Collaborators: Odense University Hospital; Zealand University Hospital; Aarhus University Hospital; Rigshospitalet, Denmark; University of Copenhagen; Hvidovre University Hospital; Bispebjerg Hospital; Vejle Hospital; Aalborg University Hospital; Herlev and Gentofte Hospital; Gødstrup Hospital; Horsens Hospital; Slagelse Hospital; Randers Regional Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): January 1, 2031

Study Registration Dates

• First Submitted: January 15, 2026
• First Submitted That Met QC Criteria: February 6, 2026
• First Posted (Actual): February 13, 2026

Study Record Updates

• Last Update Posted (Actual): February 20, 2026
• Last Update Submitted That Met QC Criteria: February 17, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Pembrolizumab; colon cancer; dMMR; neoadjuvant immunotherapy; watch-and-wait; organ sparing
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Colonic Diseases; Colonic Neoplasms; pembrolizumab
• Other Study ID Numbers: p-2025-19412

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In accordance with good academic practice and requirements of scientific journals publishing the investigation results, investigation data will be transferred in pseudonymized or anonymized format, if required, after any investigation has been completed. Data sharing will be conducted in accordance with the European data protection regulations, including the Danish Data Protection Act and the General Data Protection Regulation.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No