Clinical Study of Personalized mRNA Vaccine Encoding Neoantigen Alone in Subjects With Advanced Digestive System Neoplasms

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, feasibility, and efficacy of personalized mRNA vaccine iNeo-Vac-R01 alone in subjects with advanced digestive system neoplasms.

Detailed Description
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This is a multi-part single-center, open-label, single-arm clinical study of personalized mRNA vaccine iNeo-Vac-R01 monotherapy in subjects with advanced digestive system neoplasms. The study will include a dose escalation phase and dose expansion phase. The traditional 3+3 design will be used in dose escalation.

Official Title
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A Clinical Study to Assess the Safety, Feasibility, and Efficacy of Personalized mRNA Vaccine Encoding Neoantigen Alone in Subjects With Advanced Digestive System Neoplasms

Conditions
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Digestive System Neoplasms

Intervention / Treatment
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* Biological: iNeo-Vac-R01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, >/= 18 years old and </= 75 years old, with the ability to understand and provide signed and witnessed informed consent, and agree and are able to comply with protocol requirements. Subjects must have one of the histologically- or cytologically-confirmed advanced (locally advanced or metastatic) digestive system neoplasms, have measurable disease at study entry defined by RECIST v1.1. Subjects must have tumor progression after standard treatment or are intolerant or are unwilling to receive standard treatment. The toxic effects of previous anti-tumor treatments have returned to </= grade 1 defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 or to the level specified by the inclusion/exclusion criteria. Expected survival >/= 6 months. Eastern Cooperative Oncology Group (ECOG) performance status score of 0   2. Sufficient tumor tissue samples can be obtained from subjects for genetic analysis, with at least 2 puncture tissues with a tumor purity of ≥ 50% required for puncture samples and at least 0.5cm of tissue required for surgical samples. Alternatively, the original gene sequencing data required for tumor neoantigen analysis can be provided, including full exon sequencing data of tumor tissue, transcriptome sequencing data, and full exon sequencing data of peripheral blood. Echocardiographic evaluation: left ventricular ejection fraction (LVEF) >/= 50%. The organ function level must meet the following requirements: absolute neutrophil count (ANC) >/= 1.5 × 10^9/L, platelet count (PLT) >/= 80 × 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, TBIL </= 3 × ULN, AST, ALT </= 5 ×ULN are allowed), serum albumin >/= 28g/L, serum creatinine </= 1.5 × BUN, Glomerular filtration rate >/= 50mL/min, prothrombin time (PT) and activated partial thromboplastin time (APTT) and international standardized ratio (INR) </= 1.5 × ULN (without anticoagulant therapy) . For women of childbearing potential: having a negative serum or urine pregnancy test within 7 days prior to study initiation, agreement to remain abstinent or use contraceptive measures during the treatment period. For men: agreement to remain abstinent or use contraceptive measures during the treatment period. Exclusion Criteria: Subjects with cancer requiring anti-tumor treatment within the 5 years prior to enrollment in the study (except stage I prostate cancer, cervical cancer in situ, breast cancer in situ, papillary thyroid cancer and non-melanoma skin cancer that have been treated). Subjects who received major surgery, or had obvious traumatic injury or long-term untreated wounds or fractures within 2 weeks prior to the first dose of iNeo-Vac-R01. Subjects whose sequencing data was found that there are no new antigens available for individualized immunotherapy after analysis. Subjects who prepare to undergo or have previously received bone marrow transplantation, allogeneic organ transplantation, or allogeneic hematopoietic stem cell transplantation. Subjects who receive other anti-tumor treatments within 2 weeks prior to the first dose of iNeo-Vac-R01, including surgical treatment, chemotherapy, radiation therapy, targeted therapy, endocrine therapy, immunotherapy, biological therapy, interventional therapy, or other clinical trial related treatments. Subjects who need to use immunosuppressants, or systemic or absorbable local glucocorticoids therapy to achieve immunosuppressive effects and continue to use them within 7 days before the first administration (excluding those with daily doses of glucocorticoids less than 10mg of prednisone or doses of other therapeutic glucocorticoids equal to 10mg of prednisone). Subjects with symptomatic or untreated central nervous system metastases, except those underwent complete resection and/or radiotherapy and proven to be stable or improved (confirmed to be stable or improved for at least 4 weeks before the first dose of iNeo-Vac-R01 by CT or MRI, with no evidence of brain edema and no need for glucocorticoids or anticonvulsants. Subjects who received other vaccines within 4 weeks before the first dose of iNeo-Vac-R01, and are expected to receive other vaccines during treatment period of the study or within 60 days after the last dose of iNeo-Vac-R01. Subjects who have an active infection or uncontrollable infection requiring systemic treatment, including fungi, bacteria, viruses, or other infections; subjects with active tuberculosis; Subjects with positive hepatitis B surface antigen (HBsAg) and/or positive hepatitis B core antibody (HBcAb) and positive hepatitis B virus DNA titer detection greater than normal range; positive hepatitis C virus (HCV) antibody and HCV RNA detection greater than normal range; positive human immunodeficiency virus antibody; positive treponema pallidum-specific antibody. Subjects with autoimmune diseases or immune deficiencies treated with immunosuppressive drugs, except vitiligo, type 1 diabetes, autoimmune hypothyroidism requiring hormone treatment and psoriasis not requiring systemic treatment; known history of primary immunodeficiency. Subjects with cardiocerebrovascular events: previously or currently heart valve disease >/= grade 3, heart failure within 8 weeks before the first dose of iNeo-Vac-R01 (New York Heart Association [NYHA] cardiac function >/= grade II, myocardial infarction, unstable angina, stroke, transient ischemic attack, cardiac surgery (including coronary artery bypass grafting or percutaneous coronary intervention) within 8 weeks before the first dose of iNeo-Vac-R01, concomitant severe electrocardiogram abnormalities (such as ventricular flutter, ventricular fibrillation, multiform ventricular tachycardia, sick sinus syndrome, third degree atrioventricular block without pacemaker treatment, QTc >/= 480ms, and other conditions evaluated by the investigators as severe abnormalities), hypertension with poor drug control (systolic blood pressure >/= 160mmHg and/or diastolic blood pressure >/= 100mmHg), or other cardiocerebrovascular diseases that have been evaluated by the investigators as unsuitable for participation in this trial. Subjects with respiratory disease: previously or currently pulmonary fibrosis, interstitial lung disease, pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe asthma, pulmonary hypertension or severe impairment of lung function, etc. Subjects with moderate to severe ascites with clinical symptoms; uncontrolled or moderate to equal amounts of pleural effusion and pericardial effusion. Subjects with drug abuse; clinical or psychological or social factors that affect informed consent or research implementation. Subjects with a history of allergies to immunotherapy or vaccines, or other potential immunotherapy allergies identified by the investigators. Subjects identified that it is not suitable for enrollment or may not be able to complete this experiment for other reasons by the investigators. Vulnerable groups, including individuals with mental illness, cognitive impairment, critical patients, minors, pregnant or lactating women, etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Personalized mRNA Vaccine iNeo-Vac-R01<br>The traditional 3+3 design will be used in dose escalation. In dose escalation phase, subjects are expected to be enrolled at 50 μg, 100 μg and 150 μg (3-6 subjects in each group). The low dose group will be enrolled first. Subjects will receive iNeo-Vac-R01 administered via a hypodermic (IH) injection on Day 1 of each 21-day cycle for up to 9 cycles. The investigators will choose the optimal clinical dose for dose expansion phase. | Biological: iNeo-Vac-R01<br>* Personalized mRNA vaccine encoding neoantigen, IH injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) [safety and tolerability] |  | 21 days after last iNeo-Vac-R01 dose | 
| Proportion of Subjects Receiving iNeo-Vac-R01 Injection Treatment to Enrolled Subjects [feasibility] |  | 21 days after last iNeo-Vac-R01 dose | 
| Dose-limiting Toxicity (DLT) | Level 3 or 4 AEs related to iNeo-Vac-R01 injection. | 28 days (+/-3 days) after first iNeo-Vac-R01 dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as time between the date of the first dose of iNeo-Vac-R01 and the date of death due to any cause. | 3 years after first dose of iNeo-Vac-R01 | 
| Objective Response Rate (ORR) | ORR is defined as proportion of subjects with complete response (CR) and partial response (PR) to all subjects based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | 3 years after first dose of iNeo-Vac-R01 | 
| Disease Control Rate (DCR) | DCR is defined as proportion of subjects with reduced or stable neoplasms that have been maintained for a certain period of time, including the proportion of subjects with CR, PR, and stable disease (SD). | 3 years after first dose of iNeo-Vac-R01 | 
| Duration of Response (DOR) | DOR is defined as time from first PR or CR until either disease progression or death (whichever is sooner). | 3 years after first dose of iNeo-Vac-R01 | 
| Part A and Part B: Progression Free Survival (PFS) | PFS is defined as time between the date of first dose of iNeo-Vac-R01 and the date of either disease progression or death (whichever is sooner). | 3 years after first dose of iNeo-Vac-R01 | 
| Neoantigen-specific T Cell Response [immunogenicity] | Detect the level of specific TNF-γ in peripheral blood of subjects by ELISpot in order to measure the neoantigen-specific T cell response of subjects. | 12 months after first dose of iNeo-Vac-R01 | 
| T Cell Subsets [immunogenicity] | Detect the proportion of different T cell subsets in T cells by flow cytometry. | 12 months after first dose of iNeo-Vac-R01 | 
| Cytokines Level [immunogenicity] | Record the changes of IL-2, IL-6, IL-8, IL-10, IL-12, and TNF-α in peripheral blood before and after treatment. | 6 months after first dose of iNeo-Vac-R01 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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iNeo-Vac-R01, Personalized mRNA Vaccine, Neoantigen, Digestive System Neoplasms