YMN-A02 for Advanced pMMR Colorectal Cancer With Liver Metastases
Trial statusNot yet recruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18-70
SponsorWest China Hospital
About this trial
This study was a prospective, single-center, open-label, single-arm, multi-dose ascending phase Ⅰ clinical trial. The investigators constructed a TM10-LNP mRNA preparation encoding CTLA-4 antibody and TGF-β trap bifunction protein (YMN-A02 bifunction RNA preparation). The aim of this study is to provide a new strategy for overcoming the immune tolerance of liver tumors and improving the response rate of immunotherapy. The investigators planned to enroll patients with advanced pMMR liver metastasis from colorectal cancer who failed standard treatment. A modified "3+3" design was used, and 10 patients were expected to be enrolled. There were four dose groups of 100μg, 250μg, 500μg and 1000μg. The trial used a modified "3+3" dose climbing design, in which one subject was set as a sentinel patient in the initial 100μg dose group. If the subject did not experience DLT during the DLT observation period, the dose was judged safe and escalation to the next group occurred. If DLT occurred, 3 additional subjects in this group would be required for further evaluation. In the subsequent 250μg, 500μg, and 1000μg dose groups, three subjects were enrolled first in each group: if there was no DLT, the number of subjects was increased. If ≥2 of the 3 cases had DLT, the escalation was terminated. If DLT occurred in 1 out of 3 subjects, 3 additional observations would be made in the same dose group. If the incidence of DLT in the total 6 subjects did not exceed 1/6 after the supplement, the escalation could be escalated. Otherwise, the escalation was terminated and the dose was considered as intolerable.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Signed the informed consent form approved by the ethics committee.
18-70 years old; ECOG performance status 0-1.
Histologically or cytologically confirmed colorectal cancer with liver metastases, molecularly classified as pMMR (presence of other distant metastases allowed).
Patients who have failed or are intolerant to standard therapy, or who refuse standard therapy.
Disqualifiers
Participation in another interventional drug trial within 4 weeks before enrollment.
Prior or concurrent other malignancy, except: carcinoma in situ of the cervix, cutaneous squamous cell carcinoma, superficial bladder tumor, or any other malignancy that has been curatively treated and recurrence-free for ≥5 years.
Poorly controlled heart disease or clinical symptoms, including but not limited to: NYHA class ≥2 heart failure, unstable angina, myocardial infarction within 1 year, or clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention.
Pregnant or breastfeeding women.
Trial design
Design model
Sequential
Treatments tested in this trial
YMN-A02 100μg
Biological/VaccineEnrolled subjects will receive a 100 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.
YMN-A02 250μg
Biological/VaccineEnrolled subjects will receive a 250 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.
YMN-A02 500μg
Biological/VaccineEnrolled subjects will receive a 500 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.
YMN-A02 1000μg
Biological/VaccineEnrolled subjects will receive a 1000 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.
Treatment groups
10 Participants
are divided into 4 treatment groupsGroup A: YMN-A02 100 μg GroupExperimental treatment 1 intervention
Group B: YMN-A02 250 μg GroupExperimental treatment 1 intervention
Group C: YMN-A02 500 μg GroupExperimental treatment 1 intervention
Group D: YMN-A02 1000 μg GroupExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Occurrence of Dose-Limiting Toxicity (DLT)
Observe and record the occurrence of DLTs. DLT is defined as treatment-related adverse events or clinically significant laboratory abnormalities occurring during the DLT observation period, graded according to NCI CTCAE v5.0.
Time frame
From first dose to 14 days after the third dose, approximately Day 0 to Day 42Secondary outcomes
1
Progression-Free Survival (PFS)
Assess disease progression per RECIST v1.1, calculating the time from start of treatment to first documented disease progression or death from any cause.
Time frame
Within 2 years after the first dose2
Objective Response Rate (ORR)
Tumor response assessed per RECIST v1.1 for solid tumors. ORR is the proportion of patients whose tumor volume reduction reaches a predefined value and is maintained for a minimum required duration, calculated as the sum of complete response (CR) and partial response (PR) rates.
Time frame
Within 6 months after the first doseOther outcomes
1
Changes in Peripheral Blood Lymphocyte Subsets
Peripheral blood lymphocytes will be isolated from whole blood using lymphocyte separation medium. Flow cytometry will be used to detect T cells, B cells, macrophages, NK cells, and regulatory T cells (Tregs).
Time frame
Baseline (Day 1 pre-infusion); Day 8 (before the 2nd infusion); Day 22 (before the 4th infusion); Days 29-36 (7-14 days after the 4th infusion); Days 41-55 (19-33 days after the 4th infusion)2
Percentage of Dendritic Cells Expressing Maturation/Activation Markers
Dendritic cells (DCs) will be isolated from peripheral blood and labeled with antibodies against surface markers CD80, CD86, and MHC class II molecules. Flow cytometry will be performed to determine the percentage of DCs positive for each marker. Maturation and activation status are assessed based on these percentages
Time frame
Baseline (Day 1 pre-infusion); Day 8 (before the 2nd infusion); Day 22 (before the 4th infusion); Days 29-36 (7-14 days after the 4th infusion); Days 41-55 (19-33 days after the 4th infusion)3
Tumor-Infiltrating CD8+ T Cells
Tumor tissue sections will be stained to identify CD8+ T cells, including stem-like and exhausted CD8+ T cell subsets. Confocal microscopy and flow cytometry (using single-cell suspensions from tumor tissue) will be used to observe the infiltration status of these cells.
Time frame
Baseline (Day 1 pre-infusion); Day 8 (before the 2nd infusion); Day 22 (before the 4th infusion); Days 29-36 (7-14 days after the 4th infusion); Days 41-55 (19-33 days after the 4th infusion)4
Cytokine Levels Associated with Delayed-Type Hypersensitivity (DTH)
Plasma will be collected 24-72 hours after administration. ELISA kits will be used to measure the levels of cytokines including IL-12, IFN-γ, IL-2, and IL-10 to assess the cellular immune response and the impact of the product on immune function.
Time frame
Baseline (Day 1 pre-infusion); Day 8 (before the 2nd infusion); Day 22 (before the 4th infusion); Days 29-36 (7-14 days after the 4th infusion); Days 41-55 (19-33 days after the 4th infusion)Sponsors and contacts
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Source ClinicalTrials.gov
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