Response to Immunotherapy in MMR-deficient Localized Colon Cancer (RESET-C)

Efficacy of Immunotherapy in Patients With MMR-deficient Localized Colon Cancer Scheduled for Curative Surgery - A Prospective, Phase II Study

The aim of this study is to evaluate the safety and efficacy of neoadjuvant treatment with pembrolizumab before colonic resection in patients with early-stage (I-III) deficient mismatch repair (dMMR) colon cancer (CC).

Study Overview

• Status: Active, not recruiting
• Conditions: Colon Cancer
• Intervention / Treatment: Drug: Pembrolizumab

Detailed Description

The trial is designed as an investigator-initiated, multicenter, prospective, single arm phase II study in patients with stage I-III dMMR CC scheduled for intended curative surgery to determine the efficacy of immunotherapy using pembrolizumab in the neoadjuvant setting. Patients will receive one dose of pembrolizumab (dosage of 4mg/kg, maximum of 400mg) following diagnosis. After 3 weeks a re-evaluation (to assess tumor response) will be performed, followed by standard surgery for resection of the tumor. Surgery will therefore be performed within 3 to 5 weeks after the dose of pembrolizumab treatment. Following the surgical resection the patients may receive post-operative chemotherapy in accordance with the clinical decision. The patients will be followed as per the standard Danish guidelines with CT scans at 1 and 3 years after surgery.

• Study Type: Interventional
• Enrollment (Estimated): 85
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Camilla Qvortrup, MD, PhD; Phone Number: 35455072; Email: camilla.qvortrup@regionh.dk

Study Locations

• Denmark
  • Roskilde, Denmark
    • Zealand University Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Histologically confirmed localized dMMR stage cT1N0M0 to cT4N2M0 (stage I to III) colon carcinoma.
2. Indication for elective curative intended surgery without neoadjuvant chemotherapy.
3. Age of ≥ 18 years.
4. Written informed consent.
5. Eastern Cooperative Oncology Group performance status of 0 or 1.

6. Adequate bone marrow function defined as:

   • Hemoglobin ≥ 6.2 mmol/L or ≥ 10 g/dL.
   • Absolute neutrophil count ≥ 1.5 × 109/L.
   • Platelet count ≥ 100 × 109/L.

7. Adequate kidney function defined as:

   o Estimated glomerular filtration rate ≥ 60 mL/min or creatinine ≤1.5 × upper limit of normal (ULN).

8. Adequate liver function defined as:

   • Total bilirubin: ≤ 1.5 × ULN.
   • Alanine aminotransferase: ≤ 2.5 × ULN.
   • Alkaline phosphatase: ≤ 2.5 × ULN.

9. Follow the conditions regarding fertility, pregnancy, and lactation:

   • Female and male participants of reproductive potential (PORP) must agree to avoid becoming pregnant or impregnating a partner, respectively, while receiving pembrolizumab and for 120 days after the dose.
   • PORPs must use, or have their partner use, an acceptable method of contraception e.g. intrauterine device, contraceptive rod implanted into the skin, or hormonal contraceptive and male condom during heterosexual activity, while receiving pembrolizumab and for 120 days after the dose.
   • Women of reproductive potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L HCG) within 72 hours prior to receiving pembrolizumab.
   • Women must not be breastfeeding.

Exclusion Criteria:

1. Any serious or uncontrolled medical disorder that, in the opinion of the investigator or treating physician, may increase the risk associated with study participation, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
2. Autoimmune disorders (except thyroiditis with replacement therapy and type I diabetes mellitus).
3. Prior treatment with ICIs or any other antibody/drug specifically targeting the T-cell co-stimulation or checkpoint pathways.
4. A known history of Human Immunodeficiency Virus, active chronic, or acute Hepatitis B or Hepatitis C.
5. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
6. Prior participation in another trial with an investigational medicinal product.
7. Received live vaccines within 30 days prior to pembrolizumab trial treatment. Seasonal influenza vaccines for injection are allowed.
8. A history of allergy to study drug components or a history of severe hypersensitivity reaction to any monoclonal antibody.

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: Neoadjuvant pembrolizumab; Pembrolizumab	Drug: Pembrolizumab; One dosage of 4mg/kg (maximum of 400mg); Other Names: Keytruda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response (pCR)	Number of patients with pCR evaluated according to the Mandard tumour regression grading system	Tumour specimen evaluated within 2 weeks after surgery.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of pembrolizumab administered before surgery	Determined by the incidence and severity of treatment related adverse events according to CTCAE version 5.0	Up to approximately 9 weeks
Postoperative surgical complications	Number and severity of postoperative surgical complications determined by Clavien-Dindo classification system.	Before and up to 4 weeks after surgery
Immunohistochemistry analysis of markers including CD3, CD8, and PD-L1	Assessment of potential predictive biomarker by investigating immunological markers across pre- and post-treatment biopsies and sequential blood samples.	Baseline compared to the surgical specimen at 3-5 weeks
Methylated circulating cell-free DNA	Treatment response evaluated by methylated circulating cell-free DNA (cfDNA) specific for CC analysed across sequential blood samples using the TriMeth test	Up to approximately 9 weeks
Gene expression by mRNA	To quantify the expression of genes central to the tumour microenvironment and immune evasion of cancer among others	Baseline compared to the surgical specimen at 3-5 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
TCR sequencing	To investigate the role of the adaptive immune system in mediating the effect of pembrolizumabrepertoire, CT-scans, endoscopic photo documentation, and patient journals will be analysed with the purpose of identifying biomarkers for predicting pCR.	Baseline compared to 3-5 weeks after pembrolizumab and 2-3 weeks after surgery
CT chest/abdomen scans	Evaluated by a multidisciplinary team and centralized comity of radiologists according to the RECIST 1.1 criteria as well as cTNM staging	1-5 weeks before pembrolizumab and 3-5 weeks after pembrolizumab
Endoscopic tumour assessment	Assessed by a systematic approach including the Paris and NICE classifications	1-5 weeks before pembrolizumab and 3-5 weeks after pembrolizumab

Collaborators and Investigators

• Sponsor: Camilla Qvortrup
• Collaborators: Odense University Hospital; Zealand University Hospital; Aarhus University Hospital; Bispebjerg Hospital; Vejle Hospital; Aalborg University Hospital; Herlev and Gentofte Hospital; Horsens Hospital; Randers Regional Hospital
• Investigators: Principal Investigator: Ismail Gögenur, Professor, Zealand University Hospital; Study Director: Camilla Qvortrup, MD, PhD, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2023
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: November 24, 2022
• First Submitted That Met QC Criteria: December 14, 2022
• First Posted (Actual): December 22, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Immunotherapy; Biomarkers; dMMR; Localized colon cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: 011121

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In accordance with good academic practice, the study data (health data and genomic data) is planned to be transferred in anonymized form to the secure database European Genome-Phenome Archive (EGA). This will happen after the study has been completed. The purpose is to enable sharing of the data with other research groups for future research, inside and outside of Denmark. In all cases, data access decisions will be made by the study protocol committee. 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. The EGA is part of the European ELIXIR research infrastructure, which is partly funded by the European Commission.
• IPD Sharing Time Frame: Planned to begin approximately 6 months end ending approximately 5 years after publication of the final article.
• IPD Sharing Access Criteria: Reasonable request. In all cases, data access decisions will be made by the study protocol committee.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No