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NCT Number: NCT07409844

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

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.

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Key information

Conditions

dMMR Colorectal Cancer Colon Cancer Stage I Colon Cancer Stage II/III Colonic Diseases Colonic Neoplasms Colorectal Neoplasms Digestive System Diseases Digestive System Neoplasms Gastrointestinal Diseases Gastrointestinal Neoplasms Immunotherapy Intestinal Diseases Intestinal Neoplasms Neoplasms Neoplasms by Site Pembrolizumab

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Exclusion criteria

  • 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.
  • 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

Treatment and study plan

1 Cycle of Pembrolizumab

Drug

1 cycle of 4mg/kg (maximum of 400mg) every 6 weeks

Other names: Keytruda

2 Cycles of Pembrolizumab

Drug

2 Cycles of Pembrolizumab 4mg/kg (maximum of 400mg) every 6 weeks

Other names: Keytruda

3 Cycles of Pembrolizumab

Drug

3 Cycles of Pembrolizumab 4mg/kg (maximum of 400mg) every 6 weeks

Other names: Keytruda

Additional Cycle of Pembrolizumab

Drug

An additional 4mg/kg (maximum of 400mg) cycle of pembrolizumab in the case of non-complete response

Primary outcomes

  1. Proportion of patients with clinical complete response (cCR)

    Time frame: Periprocedural

    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.

Secondary outcomes

  1. Overall Survival (OS)

    Time frame: Up to 3 years

    Time from inclusion to death from any cause

  2. Disease-free survival (DFS)

    Time frame: Up to 3 years

    Time from inclusion to disease recurrence or death from any cause, whichever occurs first.

  3. Major patholological response (MPR) in patients undergoing surgery as per Mandard TRG

    Time frame: Perioperative

    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.

  4. Adverse events related to pembrolizumab as per Common Terminology Criteria for Adverse Events (CTCAE) v5.0

    Time frame: 1 year

    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.

  5. Adverse events related to surgery as per Clavien-Dindo (CD) classification

    Time frame: Up to 12 weeks

    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.

  6. Adverse events related to endoscopy as per American Society for Gastrointestinal Endoscopy (ASGE) lexicon

    Time frame: Periprocedural

    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).

  7. Planned or unplanned use of hospital services

    Time frame: Up to 12 weeks

    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.

  8. Change in global health status as measured by EORTC QLQ-C30

    Time frame: Up to 5 years

    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

  9. Change in CRC-related quality of life as measured by EORTC QLQ-CR29

    Time frame: Up to 5 years

    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.

  10. Change in bowel function as measured by CCBDS

    Time frame: Up to 5 years

    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.

  11. Change in overall daily function and care needs as measured by EQ-5D-5L

    Time frame: Up to 5 years

    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.

  12. Change in fatigue as measured by FACIT-Fatigue

    Time frame: Up to 5 years

    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.

  13. Change in fear of cancer recurrence as measured by FCRI-SF

    Time frame: Up to 5 years

    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.

  14. Change in post-operative recovery as measured by QoR-15

    Time frame: Up to 5 years

    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.

  15. Change in physical activity as measured by NPAQ-Short

    Time frame: Up to 5 years

    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.

  16. Change in physical fitness as measured by the 6-minute walk test

    Time frame: Up to 12 weeks

    Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in the 6-Minute Walk Test (6MWT)

  17. Change in physical fitness as measured by the sit-to-stand test

    Time frame: Up to 12 weeks

    Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in the Sit-to-Stand Test

  18. Change in physical fitness as measured by hand grip strength

    Time frame: Up to 12 weeks

    Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in hand grip strength

  19. Change in physical fitness as measured by the Borg Rating of Perceived Exertion scale

    Time frame: Up to 12 weeks

    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.

  20. Change in frailty as measured by the G8 frailty score

    Time frame: Up to 12 weeks

    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.

  21. Compliance with supervised training program

    Time frame: Up to 12 weeks

    Assessment of compliance with supervised training measured as the number of supervised training sessions attended during the intervention period

Study contacts

Contact information is provided by the study sponsor or research team.

Ismail Gögenur, Professor

CONTACT

[email protected]

+4526336426

Sponsors and collaborators

Lead sponsor

Ismail Gögenur

Other

Collaborators

  • Aalborg University Hospital
  • Aarhus University Hospital
  • Bispebjerg Hospital
  • Gødstrup Hospital
  • Herlev and Gentofte Hospital
  • Horsens Hospital
  • Hvidovre University Hospital
  • Odense University Hospital
  • Randers Regional Hospital
  • Rigshospitalet, Denmark
  • Slagelse Hospital
  • University of Copenhagen
  • Vejle Hospital
  • Zealand University Hospital

Registry information

Official study title

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

Acronym: RESET C2

Important dates

Study start
2026
Primary completion
2028
Study completion
2031
First posted
Feb 13, 2026
Registry last updated
Feb 20, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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