A Single-Arm, Open-Label, Prospective Study Evaluating the Safety, Tolerability, and Immunogenicity of the NeoOVIV Vaccine in Patients With Ovarian Cancer After Surgery
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Incidence of Treatment-Emergent Adverse Events Assessed by CTCAE Version 5.0
研究概览
简要总结
This is a Phase I, single-arm, open-label, dose-escalation study in patients with stage II or III ovarian cancer after surgery. The study will evaluate the safety, tolerability, immune response, and preliminary clinical activity of NeoOVIV, a personalized mRNA-lipid nanoparticle vaccine, when given with standard adjuvant chemotherapy and a PD-1 antibody.
详细描述
This is a Phase I, single-arm, open-label, dose-escalation study in patients with stage II or III ovarian cancer after surgery. The study will evaluate the safety, tolerability, immune response, and preliminary clinical activity of NeoOVIV, a personalized mRNA-lipid nanoparticle vaccine, when given with standard adjuvant chemotherapy and a PD-1 antibody.
Participants will receive standard postoperative chemotherapy according to clinical guidelines. Tislelizumab, a PD-1 antibody, will be given during treatment. The NeoOVIV vaccine will be made individually for each participant using tumor tissue and blood samples collected after surgery. Genetic testing will be used to identify tumor-specific neoantigens, which will then be included in the personalized vaccine.
The study will test three vaccine dose levels: 25 μg, 50 μg, and 100 μg. A traditional 3+3 dose-escalation design will be used. Each dose level will enroll 3 to 6 participants. Dose escalation will depend on whether participants develop dose-limiting toxicities after vaccination.
The NeoOVIV vaccine will be given by intramuscular injection. The planned vaccination schedule includes 9 total doses: 4 priming doses during chemotherapy and 5 booster doses after chemotherapy. Participants will be monitored closely for side effects, including injection-site reactions, fever, fatigue, immune-related adverse events, and serious organ toxicities.
The study will also assess immune responses to the vaccine using blood tests, including T-cell and B-cell analyses. Exploratory clinical outcomes will include disease-free survival, tumor marker changes, imaging results, and circulating tumor DNA testing for minimal residual disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female, aged between 18 and 75 years (inclusive) at the time of signing the written informed consent form (ICF)
- •Patients with histopathologically confirmed epithelial ovarian cancer (EOC), including: a) Patients with Stage II (Stage IIA/IIB, tumor confined to the pelvis with no extra-abdominal metastasis) or Stage III (Stage IIIA/IIIB/IIIC, tumor involving the serosal surface of intra-abdominal viscera or regional lymph node metastasis) disease, in accordance with the International Federation of Gynecology and Obstetrics (FIGO) 2014 Staging System; b) Have undergone cytoreductive surgery (CRS), with postoperative pathological confirmation of RO/R1 resection (R1 defined as microscopic residual tumor at the surgical margin ≤ 1 mm); c) Qualified tumor tissue obtained during surgery is available for neoantigen screening: ① Fresh tumor tissue ≥ 100 mg (collected on the day of surgery and immediately immersed in RNA stabilization reagent); or ② ≥ 5 unstained sections of formalin-fixed paraffin-embedded (FFPE) tissue (each with a thickness of 5 μm, tumor cellularity ≥ 30%, and no significant necrosis); d) Whole-exome sequencing (WES) combined with RNA sequencing confirms the presence of ≥ 5 "usable neoantigens" (defined as: HLA binding affinity IC50 < 500 nM, and transcript expression level of the mutant gene in transcripts per million (TPM) ≥ 1);
- •In accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, postoperative contrast-enhanced pelvic MRI/CT shows no macroscopic residual disease (R2 resection), and lung metastasis, liver metastasis, and bone metastasis are excluded;
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 to 1 (0: Fully ambulatory, no restriction in daily activities; 1: Ambulatory and able to perform light physical activity, no significant fatigue or dyspnea), with an expected overall survival of ≥ 1 year;
- •Adequate function of major organs, with relevant laboratory test results within 14 days prior to enrollment meeting the following requirements (no blood transfusion or blood product administration, no use of hematopoietic growth factors, albumin, or other blood products during this period): Hematology tests: Hemoglobin (Hb) ≥ 90 g/L; Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; Platelet count (PLT) ≥ 100 × 10⁹/L; Serum biochemistry tests: Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 × ULN; Serum creatinine (SCr) ≤ 1.5 × ULN, or creatinine clearance rate (CrCl) ≥ 50 mL/min calculated by the Cockcroft-Gault formula; Endocrine tests: Thyroid-stimulating hormone (TSH), free triiodothyronine (free T3), and free thyroxine (free T4) are within the normal reference range; Coagulation function tests: Prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤ 1.2 × ULN;
- •Women of childbearing potential (WOCBP) must have a negative serum β-human chorionic gonadotropin (β-HCG) test prior to enrollment, and agree to use effective contraceptive measures (e.g., condoms, intrauterine device [IUD]) during the study period (from the first dose administration to 6 months after the last dose administration);
- •Good treatment compliance, and the patient and their family members agree to cooperate with and complete the scheduled survival follow-up.
排除标准
- •Histopathologically confirmed non-epithelial ovarian cancer, including ovarian germ cell tumors (e.g., teratoma, yolk sac tumor), sex cord-stromal tumors (e.g., granulosa cell tumor), and metastatic ovarian tumors (e.g., Krukenberg tumor metastatic to the ovary from the gastrointestinal tract);
- •R2 resection (macroscopic residual disease) after cytoreductive surgery, or postoperative imaging (contrast-enhanced pelvic MRI/CT, chest CT) showing distant metastasis (e.g., lung, liver, brain metastasis), or FIGO stage IV disease;
- •Prior treatment with any therapeutic cancer vaccine (e.g., peptide vaccine, DNA vaccine, other mRNA vaccines); or prior use of immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies, anti-CTLA-4 antibodies) with the last dose administered ≤ 30 days before enrollment;
- •Severe surgery-related complications within 4 weeks postoperatively, including but not limited to: intra-abdominal infection requiring intravenous antibiotics for ≥ 7 days, enteric fistula requiring surgical repair, massive hemorrhage requiring transfusion ≥ 400 mL within 24 hours, severe adhesive intestinal obstruction requiring gastrointestinal decompression for ≥ 3 days;
- •Active autoimmune disease, or a history of autoimmune disease currently requiring long-term (≥ 2 weeks) immunosuppressive therapy, including but not limited to: rheumatoid arthritis requiring prednisone ≥ 10 mg/day or equivalent immunosuppressants, systemic lupus erythematosus requiring hydroxychloroquine plus glucocorticoids, ulcerative colitis with acute flare within the past 1 year, multiple sclerosis with relapse within the past 2 years, autoimmune thyroiditis requiring high-dose levothyroxine > 150 μg/day;
- •Active infection within 1 month before enrollment, including but not limited to: Bacterial infections: pneumonia requiring intravenous antibiotics, pyelonephritis with positive urine culture and fever; Viral infections: HBsAg-positive with HBV DNA ≥ 1×10³ IU/mL (untreated); HCV RNA-positive (untreated with direct-acting antivirals or persistently positive after treatment); HIV-positive; acute varicella-zoster virus (VZV) or cytomegalovirus (CMV) infection with fever or organ involvement; Fungal infections: pulmonary candidiasis, aspergillosis (confirmed by imaging and positive fungal culture);
- •Severe organ dysfunction or history thereof: acute myocardial infarction, unstable angina, heart failure (NYHA class ≥ II), severe arrhythmia (e.g., ventricular tachycardia requiring medication) within the past 6 months; uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite antihypertensive treatment); acute exacerbation of chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (CT-proven with FEV1/FVC < 70% on pulmonary function testing), active pulmonary tuberculosis (positive sputum smear or strongly positive tuberculin test without completed standard anti-tuberculosis therapy); liver cirrhosis (Child-Pugh class B or higher), active hepatitis (ALT/AST > 5×ULN), gastrointestinal bleeding within the past 1 year (e.g., esophagogastric variceal bleeding); chronic renal failure requiring dialysis or creatinine clearance < 50 mL/min (calculated by Cockcroft-Gault formula), nephrotic syndrome (24-hour urinary protein > 3.5 g);
- •Uncontrolled diabetes mellitus (fasting blood glucose ≥ 11.1 mmol/L despite hypoglycemic agents); hyperthyroidism or hypothyroidism with free T3 and free T4 remaining outside the normal range despite medical treatment;
- •Hypersensitivity to any component of the investigational products, including but not limited to: mRNA vaccine components (liposomes, poly-ICLC adjuvant), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab); or prior severe allergic reactions to similar biological agents (e.g., COVID-19 mRNA vaccines, other monoclonal antibodies) such as anaphylactic shock, laryngeal edema, bronchospasm;
- •Use of immunosuppressive agents within 2 weeks before enrollment, including but not limited to: glucocorticoids (prednisone ≥ 10 mg/day or equivalent), cyclosporine, tacrolimus, methotrexate, azathioprine; or planned use of such agents during the trial;
- •Diagnosis of another malignancy other than ovarian cancer within the past 5 years, except for cured basal cell carcinoma of the skin, cervical carcinoma in situ, and ductal carcinoma in situ of the breast, all of which must have undergone radical surgery with no recurrence;
- •Pregnant (positive serum β-HCG before enrollment) or lactating female; woman of childbearing potential refusing effective contraception during the trial (from first dose to 6 months after last dose);
- •Psychiatric disorders (e.g., dementia, major depressive disorder, schizophrenia) or cognitive impairment that prevents understanding of trial procedures or compliance with follow-up;
- •Participation in another interventional clinical trial (receipt of investigational drugs, devices, or other study interventions) within 30 days before enrollment; or currently in the follow-up period of another clinical trial without completing the final assessment;
- •Unable to provide written informed consent or unwilling to comply with trial-related requirements for personal reasons;
- •Any other condition deemed inappropriate by the investigator.
研究组 & 干预措施
Vaccine group
Participants in this arm will receive standard postoperative adjuvant therapy, tislelizumab, and the personalized NeoOVIV mRNA-lipid nanoparticle vaccine.
Standard adjuvant chemotherapy will start approximately 4 weeks after surgery according to current clinical guidelines. Tislelizumab, a PD-1 antibody, will start approximately 10 weeks after surgery and will be administered for 4 doses, generally 1 day before the corresponding chemotherapy cycle.
The NeoOVIV vaccine will start approximately 10 weeks after surgery and will be administered by intramuscular injection. Three dose levels will be evaluated using a 3+3 dose-escalation design: 25 μg, 50 μg, and 100 μg, corresponding to approximate injection volumes of 0.2 mL, 0.4 mL, and 0.8 mL, respectively. Each dose level will enroll 3 to 6 participants.
Each participant will receive 9 planned vaccine doses in total
干预措施: Low Dose NeoOVIV (Drug)
Vaccine group
Participants in this arm will receive standard postoperative adjuvant therapy, tislelizumab, and the personalized NeoOVIV mRNA-lipid nanoparticle vaccine.
Standard adjuvant chemotherapy will start approximately 4 weeks after surgery according to current clinical guidelines. Tislelizumab, a PD-1 antibody, will start approximately 10 weeks after surgery and will be administered for 4 doses, generally 1 day before the corresponding chemotherapy cycle.
The NeoOVIV vaccine will start approximately 10 weeks after surgery and will be administered by intramuscular injection. Three dose levels will be evaluated using a 3+3 dose-escalation design: 25 μg, 50 μg, and 100 μg, corresponding to approximate injection volumes of 0.2 mL, 0.4 mL, and 0.8 mL, respectively. Each dose level will enroll 3 to 6 participants.
Each participant will receive 9 planned vaccine doses in total
干预措施: Medium dose NeoOVIV (Drug)
Vaccine group
Participants in this arm will receive standard postoperative adjuvant therapy, tislelizumab, and the personalized NeoOVIV mRNA-lipid nanoparticle vaccine.
Standard adjuvant chemotherapy will start approximately 4 weeks after surgery according to current clinical guidelines. Tislelizumab, a PD-1 antibody, will start approximately 10 weeks after surgery and will be administered for 4 doses, generally 1 day before the corresponding chemotherapy cycle.
The NeoOVIV vaccine will start approximately 10 weeks after surgery and will be administered by intramuscular injection. Three dose levels will be evaluated using a 3+3 dose-escalation design: 25 μg, 50 μg, and 100 μg, corresponding to approximate injection volumes of 0.2 mL, 0.4 mL, and 0.8 mL, respectively. Each dose level will enroll 3 to 6 participants.
Each participant will receive 9 planned vaccine doses in total
干预措施: High dose NeoOVIV (Drug)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events Assessed by CTCAE Version 5.0
时间窗: From the first dose of study treatment through the last follow-up, up to 18 months
Adverse events will be assessed according to CTCAE Version 5.0. The number and percentage of participants with treatment-emergent adverse events will be reported. The onset time, grade, duration, seriousness, relationship to study treatment, management, and outcome of adverse events will be documented. Events of special interest will include injection-site reactions, fever, fatigue, headache, immune-related adverse events, and serious organ toxicities.
次要结局
- Disease-Free Survival(From the date of surgery through study completion, up to 24 months)
- Change in Tumor Marker CA125 Level(Baseline and every 4 weeks during treatment and follow-up, up to 24 months)
- Change in Tumor Marker HE4 Level(Baseline and every 4 weeks during treatment and follow-up, up to 24 months)
- Neoantigen-Specific T-Cell Response Rate Assessed by IFNγ ELISpot(Baseline preoperatively; 1 week after the third priming dose; 1 week after completion of the priming phase; 1 week after the first booster dose; and 6 months of follow-up)
- Change in CD8-Positive T-Cell Functional Subsets Assessed by Flow Cytometry(Baseline preoperatively; 1 week after the third priming dose; 1 week after completion of the priming phase; 1 week after the first booster dose; and 6 months of follow-up)
- Change in T-Cell Transcriptional Profiles Assessed by Single-Cell RNA Sequencing(Baseline preoperatively and 1 week after completion of the priming phase)
- T-Cell Clonal Expansion Assessed by TCR Sequencing(Baseline preoperatively through 12 months after treatment initiation)
- B-Cell Clonal Expansion Assessed by BCR Sequencing(Baseline preoperatively through 12 months after treatment initiation)
- Vaccine Dose Completion Rate(From the first vaccine dose through completion of the ninth planned vaccine dose, up to 26 weeks after surgery)
研究者
Xuelei Ma MD
Clinical Professor
West China Hospital