Treatment of Advanced Endocrine Tumor With Iindividualized mRNA Neoantigen Vaccine (mRNA-0523-L001)

Study Overview
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Brief Summary
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Treatment of advanced endocrine tumors, including adrenal corticocarcnioma (ACC), medullary thyroid carcinoma (MTC), thymic neuroendocrine tumor and pancreatic neuroendocrine tumor is challenging. Previous genomic profiling studies showed they presented a number of somatic mutations. The tumors Individualized mRNA neoantigen vaccine provide a promising solution since a significant portion of these tumors showed high quality of tumor specific neoantigen. The primary objective is to observe and evaluate the safety and tolerability of individualized mRNA neoantigen vaccine (mRNA-0523-L001) for the treatment of advanced endocrine tumors, failure of standard treatment or no standard treatment currently available. The secondary objective is to observe the preliminary efficacy of mRNA-0523-L001 for the treatment of advanced endocrine tumors, failure of standard treatment or no standard treatment currently available, including: Neoantigen-specific CD4+ and CD8+ T lymphocyte responses induced by mRNA-0523-L001; Objective response rate (ORR) and disease control rate (DCR) of tumors; Progression-free survival (PFS).

Official Title
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Treatment of Advanced Endocrine Tumor With Iindividualized mRNA Neoantigen Vaccine (mRNA-0523-L001)

Conditions
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Adrenal Cortical Carcinoma, Medullary Thyroid Cancer, Thymic Neuroendocrine Carcinoma, Pancreatic Neuroendocrine Tumor

Intervention / Treatment
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* Biological: individualized mRNA neoantigen vaccine (mRNA-0523-L001)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subjects voluntarily sign the written informed consent form and can comply with the visits and related procedures specified in the protocol; The subjects are 18 years old or older, regardless of gender; Patients with advanced endocrine tumors confirmed by histology or cytology in the past 6 months (including medullary thyroid carcinoma, thymic carcinoma and adrenal cortical carcinoma, etc.), who have failed standard treatment or have no standard treatment available; No HLA-related genes or chromosomal regions with copy number variations (CNVs) or loss of heterozygosity (LOH) were detected by gene sequencing; They have advanced or metastatic lesions confirmed by immunohistochemistry, and have frozen tissue/cells sufficient for WES and RNAseq sequencing, and after bioinformatics analysis, they predict at least one antigen that is effectively presented by their own HLA, such as KRAS or TP53 mutations and corresponding HLA typing, see 1.4 for the rationale of the topic. Expected survival ≥ 4 months; According to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), they have at least one measurable lesion, which should not have received local treatment such as radiotherapy (lesions in the previous radiotherapy area, if confirmed to have progressed, can also be selected as target lesions); Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1; They have not used granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), red blood cell transfusion or platelet transfusion within 14 days before the examination. Subjects of childbearing potential (male and female) who meet the inclusion criteria must agree to use reliable contraception methods (hormonal or barrier methods or abstinence) during the trial and for at least 90 days after the last administration; women of childbearing age must have a negative blood pregnancy test within 7 days before the first administration. Virology test: No CMV, EBV, HIV, HBV, HCV, syphilis infection (only at baseline) Exclusion Criteria: Received chemotherapy, hormone therapy, traditional Chinese medicine with anti-tumor indications or other anti-tumor treatments within 4 weeks before the first administration (for mitomycin and nitrosourea, the last administration was within 6 weeks before the first administration of this study drug), or within 5 half-lives of immunotherapy or molecular targeted therapy; Received other major surgery other than diagnosis or biopsy within 4 weeks before the first administration, or expected to receive major surgery during the study; Patients who have received allogeneic hematopoietic stem cell transplantation or organ transplantation in the past, or plan to receive organ transplantation during this study; Patients who have received other tumor vaccines or cell therapies in the past; Medical condition Patients with clinically symptomatic brain metastases, spinal cord compression, carcinomatous meningitis, or other evidence indicating that the patient's brain or spinal cord metastases are not controlled, and are deemed unsuitable for enrollment by the investigator; In the past 2 years, there have been known other malignant tumors that are progressing or require active treatment (except for non-melanoma skin cancer, superficial bladder cancer, and cervical carcinoma in situ that have been cured by radical surgery); Have a history of interstitial lung disease (ILD) or pulmonary interstitial fibrosis; Have a history of severe cardiovascular and cerebrovascular diseases, including but not limited to: a) Have severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, II-III degree atrioventricular block; corrected QTc interval male > 450 milliseconds, female > 470 milliseconds, b) Acute coronary syndrome, congestive heart failure, aortic dissection, stroke or other grade 3 or higher cardiovascular and cerebrovascular events occurred within 6 months before the first administration, c) New York Heart Association (NYHA) ≥ III grade heart failure or left ventricular ejection fraction (LVEF) <50%. Other serious and/or uncontrollable diseases that may affect the subject's participation in this study, as determined by the investigator, including but not limited to: a) Have a history of severe drug allergy, or known to be allergic to any component of the tumor vaccine; or have had a severe allergic reaction to other monoclonal antibodies in the past, b) Have a history of immunodeficiency, including HIV positive or other acquired or congenital immunodeficiency diseases, c) Evidence of severe or uncontrolled liver or kidney disease, d) Poorly controlled hypertension, diabetes, etc., e) Patients with active ulcers or gastrointestinal bleeding f) Have a severe infection that requires intravenous infusion of antibiotics or hospitalization; or uncontrolled active infection within 4 weeks before the first administration, g) Have active syphilis infection. Participated in other clinical trials within 4 weeks before the first administration (except for screening failure); Currently receiving systemic use of corticosteroids (except for recent or current use of inhaled corticosteroids); Pregnant or lactating women; Laboratory and imaging examinations Imaging (CT or MRI) shows that the tumor invades the large blood vessels and has a tendency to bleed; Have clinically significant thyroid function abnormalities, and the investigator deems them unsuitable for enrollment; Active pneumonia was found in the screening chest CT scan; Uncontrolled pleural effusion, pericardial effusion, or ascites that requires repeated drainage; The adverse reactions of previous anti-tumor treatment have not recovered to NCI-CTCAE 5.0 grade evaluation ≤ 1 (except for hair loss); Hepatitis B surface antigen (HBsAg) positive and peripheral blood hepatitis B virus deoxyribonucleic acid (HBV DNA) test value higher than the upper limit of normal; hepatitis C virus antibody (HCV Ab) positive and HCV RNA test value higher than the upper limit of normal; Investigator assessment The investigator considers that there are other reasons that are not suitable for participating in the clinical trial.

Ages Eligible for Study
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Minimum Age: 18 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: mRNA-0523-L001<br>individualized mRNA neoantigen vaccine (mRNA-0523-L001) | Biological: individualized mRNA neoantigen vaccine (mRNA-0523-L001)<br>* Individualized mRNA neoantigen vaccine (mRNA-0523-L001) will be injected intramuscularly every 21 days for 9 cycles. Dose escalation will be administered in 3 patients. 18 additional patients will be recruited and administered at the maximum tolerated(MTD) dose for all nine cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) or Dose-limiting toxicity (DLT).If MTD is not reached, Biologically Effective Dose (BED)tumor neoantigen. | The highest dose of a drug or treatment that does not cause unacceptable side effects. | At the end of cycle 1(each cycle is 21 days) | 
| Incidence of treatment-related adverse events. | According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). | At the end of cycle 1(each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reaction of antigen-specific T cells in peripheral blood. | mRNA-0523-L001 personalized tumor vaccine induces neoantigen specific CD4+and CD8+T lymphocyte responses. | At the end of cycle 1(each cycle is 21 days) | 
| Objective tumor response rate (ORR) | ORR calculates the ratio of the number of patients whose best response is complete remission (CR) or partial remission (PR) to the total number of evaluable patients according to RECIST 1.1 criteria. Those who have not been evaluated for lesion and tumor response will be regarded as non-evaluable patients and will not be counted. | At the end of cycle 1(each cycle is 21 days) | 
| Disease control rate (DCR) | DCR calculates the ratio of the number of patients whose best response is complete remission (CR), or partial remission (PR), or stable disease (SD) to the total number of evaluable patients according to RECIST 1.1 criteria. Those who have not been evaluated for lesion and tumor response will be regarded as non-evaluable patients and will not be counted. | At the end of cycle 1(each cycle is 21 days) | 
| Progressive free survival (PFS) | Progression-free Survival of Personalized mRNA Tumor Vaccine. | At the end of cycle 1(each cycle is 21 days) |