RESET-C: Response to Immunotherapy in MMR-deficient Localized Colon Cancer
Study Details
Study Description
Brief Summary
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Neoadjuvant pembrolizumab Pembrolizumab |
Drug: Pembrolizumab
One dosage of 4mg/kg (maximum of 400mg)
Other Names:
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Outcome Measures
Primary Outcome Measures
- Pathological complete response (pCR) [Tumour specimen evaluated within 2 weeks after surgery.]
Number of patients with pCR evaluated according to the Mandard tumour regression grading system
Secondary Outcome Measures
- Safety and tolerability of pembrolizumab administered before surgery [Up to approximately 9 weeks]
Determined by the incidence and severity of treatment related adverse events according to CTCAE version 5.0
- Postoperative surgical complications [Before and up to 4 weeks after surgery]
Number and severity of postoperative surgical complications determined by Clavien-Dindo classification system.
- Immunohistochemistry analysis of markers including CD3, CD8, and PD-L1 [Baseline compared to the surgical specimen at 3-5 weeks]
Assessment of potential predictive biomarker by investigating immunological markers across pre- and post-treatment biopsies and sequential blood samples.
- Methylated circulating cell-free DNA [Up to approximately 9 weeks]
Treatment response evaluated by methylated circulating cell-free DNA (cfDNA) specific for CC analysed across sequential blood samples using the TriMeth test
- Gene expression by mRNA [Baseline compared to the surgical specimen at 3-5 weeks]
To quantify the expression of genes central to the tumour microenvironment and immune evasion of cancer among others
Other Outcome Measures
- TCR sequencing [Baseline compared to 3-5 weeks after pembrolizumab and 2-3 weeks after surgery]
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.
- CT chest/abdomen scans [1-5 weeks before pembrolizumab and 3-5 weeks after pembrolizumab]
Evaluated by a multidisciplinary team and centralized comity of radiologists according to the RECIST 1.1 criteria as well as cTNM staging
- Endoscopic tumour assessment [1-5 weeks before pembrolizumab and 3-5 weeks after pembrolizumab]
Assessed by a systematic approach including the Paris and NICE classifications
Eligibility Criteria
Criteria
Inclusion Criteria:
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Histologically confirmed localized dMMR stage cT1N0M0 to cT4N2M0 (stage I to III) colon carcinoma.
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Indication for elective curative intended surgery without neoadjuvant chemotherapy.
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Age of ≥ 18 years.
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Written informed consent.
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Eastern Cooperative Oncology Group performance status of 0 or 1.
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Adequate bone marrow function defined as:
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Hemoglobin ≥ 6.2 mmol/L or ≥ 10 g/dL.
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Absolute neutrophil count ≥ 1.5 × 109/L.
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Platelet count ≥ 100 × 109/L.
- Adequate kidney function defined as:
o Estimated glomerular filtration rate ≥ 60 mL/min or creatinine ≤1.5 × upper limit of normal (ULN).
- Adequate liver function defined as:
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Total bilirubin: ≤ 1.5 × ULN.
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Alanine aminotransferase: ≤ 2.5 × ULN.
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Alkaline phosphatase: ≤ 2.5 × ULN.
- Follow the conditions regarding fertility, pregnancy, and lactation:
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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.
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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.
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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.
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Women must not be breastfeeding.
Exclusion Criteria:
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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.
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Autoimmune disorders (except thyroiditis with replacement therapy and type I diabetes mellitus).
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Prior treatment with ICIs or any other antibody/drug specifically targeting the T-cell co-stimulation or checkpoint pathways.
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A known history of Human Immunodeficiency Virus, active chronic, or acute Hepatitis B or Hepatitis C.
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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.
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Prior participation in another trial with an investigational medicinal product.
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Received live vaccines within 30 days prior to pembrolizumab trial treatment. Seasonal influenza vaccines for injection are allowed.
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A history of allergy to study drug components or a history of severe hypersensitivity reaction to any monoclonal antibody.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Camilla Qvortrup
- Zealand University Hospital
- Odense University Hospital
- Vejle Hospital
- Herlev and Gentofte Hospital
- Bispebjerg Hospital
- Aalborg University Hospital
- Horsens Hospital
- Randers Regional Hospital
- Aarhus University Hospital
Investigators
- Study Director: Camilla Qvortrup, MD, PhD, Rigshospitalet, Denmark
- Principal Investigator: Ismail Gögenur, Professor, Zealand University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 011121