Response to Immunotherapy in MMR-deficient Localized Colon Cancer

Colon Cancer Clinical Trial

— RESET-C  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05662527
• Other study ID #: 011121
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: February 22, 2023
• Est. completion date: July 2027

Study information

• Verified date: March 2024
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 85
• Est. completion date: July 2027
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colon Cancer
• Colonic Neoplasms

Intervention

Drug:
• Pembrolizumab
One dosage of 4mg/kg (maximum of 400mg)

Locations

Country	Name	City	State
Denmark	Zealand University Hospital	Roskilde

Sponsors (10)

Lead Sponsor	Collaborator
Camilla Qvortrup	Aalborg University Hospital, Aarhus University Hospital, Bispebjerg Hospital, Herlev and Gentofte Hospital, Horsens Hospital, Odense University Hospital, Randers Regional Hospital, Vejle Hospital, Zealand University Hospital

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Primary	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	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
Secondary	Postoperative surgical complications	Number and severity of postoperative surgical complications determined by Clavien-Dindo classification system.	Before and up to 4 weeks after surgery
Secondary	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
Secondary	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
Secondary	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