Exploratory Clinical Study of Personalized mRNA Tumor Vaccine RH125 in Patients With Advanced Solid Tumors

This study will be divided into monotherapy dose escalation and combination therapy dose escalation phases. Each phase requires the enrollment of 12-18 subjects, with a total of 24-36 subjects to be enrolled in the entire study. Both the monotherapy dose escalation and combination therapy dose escalation will involve 3 dose levels, which are 100 μg, 150 μg, and 200 μg respectively. A "3+3" design will be adopted, and the Dose-Limiting Toxicity (DLT) observation period will be 21 days for both phases.

Inclusion criteria

• Male or female, aged from 18 to 70 years old.
• Patients with histologically and radiologically confirmed locally advanced or metastatic solid tumors that are not suitable for curative surgical treatment, Eligible patients must have experienced disease progression following standard antitumor therapy or be unable or unwilling to receive standard treatments. Patients in the combination therapy group are suitable for PD-1 blockers therapy judged by the investigator .
• Patients must hava at least one measureble disease per RECIST 1.1.
• Patients must have a fresh tumor lession sample for sequencing and test of expression of PD-1(22c3,only for patients in the combination therapy group .)
• ECOG performance status of 0 or 1
• Life expectancy of at least 6 months.
• Adequate organ and hematologic function, with no severe dysfunction of the heart, lungs, liver, kidneys, or immune system, based on the following laboratory values:

1). Hematology: ANC ≥ 1.5 × 10⁹/L, PLT ≥ 100 × 10⁹/L, HGB ≥ 100 g/L. Within one week before screening, the subject must not have received blood or platelet transfusions, G-CSF, or erythropoietin (EPO); 2). Renal function: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min (calculated using the Cockcroft-Gault formula); 3). Liver function: AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver cancer or liver metastases); TBIL ≤ 1.5 × ULN (patients with Gilbert's syndrome: TBIL < 3 × ULN); 4). Coagulation: INR ≤ 1.5 × ULN or APTT ≤ 1.5 × ULN (except for patients on anticoagulants).

8.. Male subjects with reproductive potential and female subjects of childbearing potential agree to use effective contraception from the time of informed consent until 6 months after the last dose of investigational drug.

Women of childbearing potential include premenopausal women and those within 2 years post-menopause.

A negative serum pregnancy test is required within 7 days before the first dose of the investigational product.

Exclusion criteria

• Having active malignant tumors within 2 years before the first administration, except for any locally curable tumors that have received radical treatment (e.g., resected basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix or breast);
• Presecne of central nervous system metastases, carcinomatous meningitis, or primary central nervous system tumors.
• Results of predicted neoantigen epitopes is less than 5.
• Having received other anti-tumor treatments (such as chemotherapy, endocrine therapy, targeted therapy, immunotherapy, radiotherapy, or tumor embolization) within 4 weeks before the first vaccination; for oral fluoropyrimidines and small-molecule targeted drugs, the interval required is more than 2 weeks or 5 half-lives of the drug, whichever is longer.
• Clinically significant residual toxicity (≥ grade 2 per CTCAE v5.0) from previous treatment (including systemic therapy, radiotherapy, or surgery), except for alopecia, hyperpigmentation, or other AEs deemed by the investigator not to affect study safety and where recovery to grade ≤1 is not required.
• Prior one marrow transplantation, allogeneic hematopoietic stem cell transplantation or solid organ transplantation
• Patients who need to take immunosuppressants regularly within 4 weeks before the first vaccination and during the clinical study, including but not limited to the following situations: those with severe asthma, autoimmune diseases or immunodeficiency, those receiving immunosuppressive drug therapy, or those with a known history of primary immunodeficiency; however, subjects with the following diseases are allowed to undergo further enrollment screening: type I diabetes with good control, hypothyroidism with good control requiring only hormone replacement therapy, skin diseases that do not require systemic treatment (such as vitiligo, psoriasis or alopecia), or subjects whose condition is not expected to relapse without external triggers.
• Clinically diagnosed active bacterial or fungal infections; having active tuberculosis or a history of tuberculosis.
• Active hepatitis B virus (HBV) infection (defined as HBsAg positive and HBV-DNA > ULN), hepatitis C virus (HCV) infection (defined as HCV-Ab positive and HCV-RNA positive), human immunodeficiency virus (HIV) infection (HIV-Ab positive) or treponema pallidum(TP) infection.
• Severe cardiovascular diseases occurring within 2 years before the first administration, including but not limited to: stable angina pectoris with functional class III-IV; unstable angina pectoris or myocardial infarction; NYHA class III-IV congestive heart failure; severe arrhythmias requiring drug treatment.
• A history of substance abuse, or clinical, psychological, or social factors that may affect informed consent or the conduct of the study; a history of mental illness.
• A history of allergies to previous vaccinations, allergies to any component of the investigational product, a history of severe allergies to food or drugs, or other potential allergies to immunotherapy as deemed by the investigator.
• Pregnant or lactating women.
• Participation in other interventional clinical studies within 12 weeks before the first vaccination, except for participation in observational (non-interventional) clinical studies or being in the survival follow-up phase of interventional studies.
• Vaccination of any type within 28 days before administration.
• Subjects deemed unsuitable for enrollment by the investigator or who may be unable to complete the trial for other reasons.