Immunotherapy in Patients With Early dMMR Rectal Cancer (RESET-R)

The purpose of this investigator-initiated, multicenter phase II trial is to evaluate the efficacy and tolerability of nivolumab and ipilimumab in patients with stage 1-3 MSI/dMMR rectal cancer.

The primary objective is:

Number of patients with complete clinical response after one or two cycles of immunotherapy.

Patients will be treated with 1 or 2 cycles of combination immunotherapy:

Cycle 1: Nivolumab 3 mg/kg days 1 and 15 & ipilimumab 1 mg/kg day 1 Cycle 2: Nivolumab 3 mg/kg days 50 and 65 & ipilimumab 1 mg/kg day 50

Study Overview

• Status: Recruiting
• Conditions: Cancer of Rectum
• Intervention / Treatment: Drug: Nivolumab; Drug: Ipilimumab

• Study Type: Interventional
• Enrollment (Estimated): 39
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Christian P Olsen, Phd; Phone Number: 24342488; Email: Christian.pilely.olsen@rsyd.dk
• Study Contact Backup: Name: Julie Bach; Phone Number: 30714320; Email: Julie.Kristina.Bach@rsyd.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Recruiting
    • Aalborg University Hospital
    • Contact: laurids Ø Poulsen, MD
  • Aarhus, Denmark, 8200
    • Recruiting
    • Aarhus University Hospital
    • Contact: Claus L Andersen, MD
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Rigshospitalet
    • Contact: Vinicius Lima, MD
  • Odense, Denmark, 5000
    • Recruiting
    • Department of Oncology, Odense University Hospital
    • Contact: Line S Tarpgarrd, MD; Phone Number: +45 6541 2921; Email: line.tarpgaard@rsyd.dk
    • Principal Investigator: Line S Tarpgarrd, MD
  • Roskilde, Denmark, 4000
    • Recruiting
    • Zealand University Hospital
    • Contact: Ismail Gögenur, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years.
• Histologically verified non-metastatic rectal cancer stage 1-3.
• No indication for local therapy like TEM.
• Histologically verified dMMR or MSI.
• Performance status (WHO) of 0-1.
• No previous chemotherapy, radiotherapy or immunotherapy for colorectal cancer
• Adequate haematological function defined as neutrophils ≥ 1.5 x 109/l and platelets ≥ 100 x 109/l.
• Adequate organ function (bilirubin ≤ 1.5 x UNL (upper normal limit), GFR (may be calculated) > 30 ml/min.
• Women of childbearing potential must have been tested negative in a serum pregnancy test within five days prior to registration. Fertile patients must agree to use a highly effective method of birth control. (i.e., pregnancy rate of less than 1 % per year) (Appendix 1) during the study and for six months after the discontinuation of study medication.
• Has provided written informed consent prior to performance of any study procedure.
• Written informed consent must be obtained according to the local Ethics Committee requirements.

Exclusion Criteria:

• Any other condition or therapy, which in the investigator's opinion may pose a risk to the patient or interfere with the study objectives.
• Concomitant use of systemic glucocorticoids more than the equivalent dose to tablet prednisolone 10 mg/day. Treatment with systemic glucocorticoids must end no later than two weeks before inclusion.
• Subjects with active, known, or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol.
• Known allergy or intolerance to any of the drugs used (nivolumab and ipilimumab).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: nivolumab + ipilimumab; Patients will be treated with 1 or 2 cycles of combination immunotherapy: Cycle 1: Nivolumab 3 mg/kg days 1 and 15 & ipilimumab 1 mg/kg day 1 Cycle 2: Nivolumab 3 mg/kg days 50 and 65 & ipilimumab 1 mg/kg day 50

Drug: Nivolumab; Nivolumab is a highly selective fully humanized, IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1) (17). PD-1 is an inhibitory receptor expressed on the surface of T-cells, B cells, macrophages, and NK cells. Endogenous binding of PD-1 with one of its two ligands PD-L1 and PD-L2 results in production of an inhibitory signal which results in reduction of T-cell proliferation, cytokine production, and cytotoxic activity. This results in significant dampening of the immune response. Nivolumab acts to selectively block the receptor activation of PD-L1 and PD-L2, resulting in a release of PD-1 mediated inhibition of the immune response.; Other Names: Opdivo; Drug: Ipilimumab; Ipilimumab is a fully humanized monoclonal anti-CTLA-4 antibody that acts as an antineoplastic ICI by selectively binding to cytotoxic T-lymphocyte-associated antigen 4, a molecule located on the surface of cytotoxic T-cells, suppressing the immune response (17). Ipilimumab blocks CTLA-4, leading to a continuously active immune response in malignant cells.; Other Names: Yervoy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete clinical response	Proportion of patients with complete clinical response Complete clinical response will be defined as no visible or palpable tumor examined by rectal exploration (if low tumors), endoscopy and MR-scan. Patients with definite but less than complete regression BUT with a representative biopsy without viable tumor cells will also be classified as cCR in this trial.	Evaluated at day 93 (+/- 7 days) after one or two cycles of immunotherapy. (Each cycle is 7 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete biological response	Proportion of patients with complete biological response	Evaluated at day 93 (+/- 7 days) after one or two cycles of immunotherapy. (Each cycle is 7 weeks)
12 months recurrence	Proportion of patients without any sign of recurrence after 12 months.	after 12 months
Respons rate	Response rate according to mrTRG.	after 1 or 2 cycles of immunotherapy. (Each cycle is 7 weeks)
Adverse events	Adverse events assessed by the investigator according to the definitions in NCI-CTC, version 5.0	after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks)
Bio-marker predictive models for treatment response and survival.	Correlation between bio-markers (ctDNA and CEA) and outcome.	after 1 or 2 cycles of immunotherapy. (Each cycle is 7 weeks)
Quality of life (EORCT QLQ-C30)	Change in Quality of life (EORCT QLQ-C30)	after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks)
Quality of life (EORCT QLQ-CR29)	Change in Quality of life (EORCT QLQ-CR29)	after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks)

Collaborators and Investigators

• Sponsor: Odense University Hospital
• Collaborators: Zealand University Hospital; Aarhus University Hospital; Rigshospitalet, Denmark; Bispebjerg Hospital; Vejle Hospital; Aalborg University Hospital; Herlev and Gentofte Hospital
• Investigators: Principal Investigator: Line S Tarpgaard, MD, Phd, Department of Oncology, Odense University Hospital, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2023
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): February 1, 2052

Study Registration Dates

• First Submitted: January 17, 2023
• First Submitted That Met QC Criteria: February 7, 2023
• First Posted (Actual): February 17, 2023

Study Record Updates

• Last Update Posted (Actual): August 7, 2025
• Last Update Submitted That Met QC Criteria: August 1, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Rectal Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Nivolumab; Ipilimumab
• Other Study ID Numbers: KFE nr. 22.20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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