Safety and Efficacy of Personalized Neoantigen Vaccine in Advanced Solid Tumors

A Dose-Escalation and Dose-Expansion Study Evaluating the Safety and Efficacy of Personalized Neoantigen Vaccine in Advanced Solid Tumors

This trial is an investigator-initiated, single-center, open-label, single-arm exploratory study of mRNA personalized neoantigen tumor vaccine in the treatment of advanced solid tumors, including two phases: dose escalation and dose expansion. The main objective is to evaluate the safety and tolerability of personalized neoantigen tumor vaccine in subjects with advanced solid tumors, and secondary objective is to preliminarily evaluate the efficacy of personalized neoantigen tumor vaccine in subjects with advanced solid tumors. According to the characteristics of safety and efficacy data in the dose escalation phase, the dose expansion is performed at the intended clinical dose based on the investigator's judgment, and the treatment will be performed in combination with PD-1 to further evaluate the efficacy and safety profile of personalized neoantigen tumor vaccine at a specific dose.

Both the dose escalation phase and dose expansion phase include a screening period (Week -4 ~ Week -2), a baseline period (Week -1 ~ Day -1), a treatment period (Day 1 ~ Week 8 or 16), and a follow-up period. Subjects who signed and provided the formal informed consent entered the screening period. The treatment period included the initial treatment period (Day 1 ~ Week 8) and the enhanced treatment period (Week 12 ~ Week 16). The investigator determine if the subject is suitable to enter the enhanced treatment period based on the comprehensive judgment of the subject's efficacy, safety, compliance and other factors.

Dose escalation phase is the traditional 3 + 3 design,, 12-18 subjects are expected to be enrolled at 100 μg, 200 μg and 400 μg (3-6 subjects in each group). The low dose group will be enrolled first.

The investigator will choose the optimal clinical dose for dose expansion, which can be one dose group or multiple dose groups. PD-1 will be administered in parallel to further confirm the efficacy and safety of neoantigen tumor vaccine. About 18 subjects will be enrolled. The usage and dosage of PD-1 should aligned with the package insert.

Inclusion Criteria:

1. Voluntarily signed and provided formal informed consent;
2. Male and female patients aged 18-75 years (inclusive);
3. Expected survival ≥ 3 months;
4. Subject with advanced solid tumor proved by histopathology or cytology and who have failed to respond to standard treatment;
5. At least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors RECIST v1.1 (see Appendix 4, Response Evaluation Criteria in Solid Tumors) (i.e., mass ≥ 10 mm in diameter and malignant lymph node ≥ 15 mm in short diameter on enhanced spiral CT ≤ 5 mm);
6. ECOG performance status score of 0 ~ 2;
7. Treatment with other antineoplastic agents (e.g., chemotherapy, hormonal therapy, immunotherapy, antibody therapy, radiotherapy) for more than 5 half-lives of this agent or more than 4 weeks from baseline (whichever is shorter) during the baseline period ;
8. The organ function level must meet the following requirements (no blood transfusion or blood products, no hematopoietic stimulating factors, no albumin or blood products): absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, platelet count (PLT) ≥ 75 × 10^9/L, hemoglobin (Hb) ≥ 90 g/L; serum total bilirubin (TBIL) ≤ 1.5 ×ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5×ULN (if there is liver metastasis, total bilirubin ≤ 3 ×ULN, AST, ALT ≤ 5 ×ULN are allowed); Note: These laboratory tests may only be repeated once if the investigator deems it necessary (the reason for retest must be documented). If the criteria are met after retest, the laboratory parameter can be considered qualified.
9. Premenopausal women of childbearing potential must have a negative pregnancy test within 7 days prior to initiation of treatment and be non-lactating; women of non-childbearing potential are not required to have a pregnancy test and contraception unless participants are 50 years of age or older, have not used hormonal therapy and have been amenorrheic for at least 12 months, or have been surgically sterilized. All subjects (male or female) should use adequate barrier contraception throughout treatment and for 3 months after the end of treatment.

Exclusion Criteria:

1. Subject who need to receive systemic application of anti-allergic drugs for a long time, or have a history of life-threatening allergic reactions to any vaccine or drug;
2. Symptomatic or rapidly progressive central nervous system metastases. Patients with extensive lung metastases resulting in dyspnea; patients with tumors close to or invading major blood vessels or nerves;
3. New cerebrovascular accident (including ischemic stroke, hemorrhagic stroke, and transient ischemic attack) within 6 months before screening;
4. Subject with acute myocardial infarction within 6 months before screening, or uncontrolled angina, uncontrolled arrhythmia, severe heart failure (see Appendix 3, New York Heart Association Heart Failure Classification Criteria NYHA Class ≥ III) and other cardiovascular diseases;
5. Subject who have received treatment with immunomodulatory drugs 4 times before the first vaccination day (D1), including but not limited to: IL-2, CTLA-4 inhibitors, CD40 agonists, CD137 agonists, IFN-α (except for high-risk surgical subjects who use IFN-α as adjuvant therapy, if IFN-α treatment is stopped 4 times before this trial); Subject with a history of renal insufficiency, serum creatinine level greater than 1.5 times the upper limit of normal;
6. Subject who received blood transfusion, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) before baseline;
7. Subject with skin diseases (e.g., psoriasis) at baseline that may prevent the intradermal injection of vaccine into the target area;
8. Subject still suffer from adverse reactions (except alopecia and platinum-induced neurotoxicity ≤ grade 2) that have not been restored to CTCAE version 5.0 grade ≤ 1 after previous anti-tumor treatment during the screening period;
9. Concomitant use of steroid hormone drugs (tumor or non-tumor related diseases) is required; however, topical application (not applied to the vaccination site) or inhaled steroid drugs are required;
10. Subject has an active infection or uncontrollable infection (except for simple urinary tract infection or upper respiratory tract infection) requiring systemic treatment; subjects with positive human immunodeficiency virus antibody, hepatitis B surface antigen and/or hepatitis B core antibody and positive hepatitis B virus deoxyribonucleic acid > 10^3 IU/mL, hepatitis C virus antibody, Treponema pallidum-specific antibody in virological monitoring during the screening period;
11. Hypertension poorly controlled on treatment (defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg);
12. Subject with other malignant tumors within 5 years before the screening period, except for cervical carcinoma in situ, breast carcinoma in situ and cutaneous basal cell carcinoma that have received appropriate treatment and met the recovery criteria;
13. Subject with a history of autoimmune diseases [such as, but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (hypothyroidism without clinical symptoms or hypothyroidism caused by chemoradiotherapy can be included), subjects with vitiligo or recovered asthma can be included without any intervention, and subjects with asthma requiring bronchodilators for medical intervention cannot be included];
14. Subject with active ulcer or gastrointestinal bleeding during the screening period;
15. Subject who has previously received similar therapeutic tumor vaccines;
16. Subject with congenital or acquired immunodeficiency;
17. Subjects with congenital or acquired immunodeficiency;
18. Subjects who are still involved in other clinical trials and have not been enrolled during the screening period;
19. Known active pulmonary tuberculosis (TB). Subjects suspected of active TB should be examined for chest imaging and excluded from clinical symptoms and signs;
20. Major surgical procedure (defined by the investigator as open biopsy, significant trauma, etc) within 4 weeks prior to the first dose of study drug. Note: Replacement of intravenous infusion dropper is acceptable. Has a major surgical plan within 30 days of the first dose, at the discretion of the investigator, or has not fully recovered from prior surgery. Local surgery (e.g., placement of a systemic port, core needle biopsy, and prostate biopsy) is permitted provided it was completed at least 24 hours prior to the first dose of study treatment;
21. Subjects who, in the opinion of the investigator, have an underlying health condition, mental condition or social situation and are unable or unwilling to comply with the study protocol;
22. Other severe, acute or chronic medical condition or psychiatric condition or laboratory abnormality that, in the judgment of the investigator, may increase the risk associated with study participation or may interfere with the interpretation of study results.