A Single-Arm, Open-Label, Prospective Study Evaluating the Safety, Tolerability, and Immunogenicity of the NeoOVSV Vaccine in Patients With Ovarian Cancer After Surgery

Обзор

This is a Phase I, single-arm, open-label, prospective, non-randomized, single-center dose-escalation study. The study will evaluate the safety, tolerability, and preliminary activity of the NeoOVSV mRNA-lipid nanoparticle vaccine in patients with stage II/III ovarian cancer after surgery, in combination with standard adjuvant chemotherapy and a PD-1 antibody.

Подробное описание

\*\*Study Overview\*\*

This is a Phase I, single-arm, open-label, prospective, non-randomized, single-center dose-escalation study. The study will evaluate the safety, tolerability, and preliminary activity of the NeoOVSV mRNA-lipid nanoparticle vaccine in patients with stage II/III ovarian cancer after surgery, in combination with standard adjuvant chemotherapy and a PD-1 antibody.

\*\*Study Population\*\*

Eligible participants are patients with FIGO 2014 stage II or III ovarian cancer who have undergone R0 or R1 surgical resection and have not yet started other adjuvant therapy within 4 weeks after surgery.

\*\*Dose-Escalation Design\*\*

The study uses a traditional "3+3" dose-escalation design. Three dose levels of the NeoOVSV vaccine will be tested:

* Dose Level 1: 25 μg * Dose Level 2: 50 μg * Dose Level 3: 100 μg

Each dose level will initially include 3 participants. If no participant develops dose-limiting toxicity (DLT) within 28 days after the first vaccination, the study will proceed to the next dose level. If 1 of 3 participants develops DLT, 3 additional participants will be enrolled at the same dose level. If 2 or more participants at a dose level develop DLT, dose escalation will stop, and the previous dose will be considered the maximum tolerated dose within the planned dose range.

If no maximum tolerated dose is reached after evaluation of the 100 μg dose level, 100 μg will be considered the highest tested dose. The recommended dose for future studies will be selected based on overall safety, tolerability, immune response, feasibility, and clinical findings.

\*\*Treatment Plan\*\*

Participants will receive standard adjuvant chemotherapy, a PD-1 antibody, and the NeoOVSV vaccine.

Standard chemotherapy will start approximately 4 weeks after surgery, according to current clinical guidelines. Tislelizumab, a PD-1 antibody, will also start approximately 4 weeks after surgery and will be given for 6 doses, usually before chemotherapy.

The NeoOVSV vaccine will be given by intramuscular injection. The preferred injection site is the deltoid muscle of the upper arm. Other suitable intramuscular injection sites may be used when needed.

The vaccine schedule includes:

* \*\*Priming phase:\*\* 1 injection every 3 weeks during chemotherapy, for a total of 6 doses * \*\*Booster phase:\*\* 1 injection every week after chemotherapy, for a total of 3 doses

Each participant will receive only one assigned vaccine dose level.

\*\*Study Vaccine\*\*

NeoOVSV is a shared-antigen mRNA-lipid nanoparticle vaccine. It contains mRNA sequences encoding seven ovarian cancer-associated antigens:

FOLR1, MUC16, CLDN6, MSLN, WT1, PRAME, and MAGEA4.

The mRNA is formulated in lipid nanoparticles to protect the mRNA and support delivery to immune cells. The vaccine will be manufactured and released according to GMP quality standards before use in the study.

\*\*Main Study Assessments\*\*

The primary objective is to assess safety and tolerability. Adverse events will be monitored and graded according to CTCAE v5.0. The study will closely monitor injection-site reactions, fever, fatigue, headache, and immune-related adverse events such as rash, thyroid dysfunction, colitis, pneumonitis, or myocarditis.

DLT will be assessed during the first 28 days after vaccination. DLT may include severe treatment-related toxicity, grade 4 adverse events, serious organ toxicity, or adverse events that cause treatment interruption.

Secondary and exploratory assessments include immune response, preliminary clinical activity, and feasibility. Blood samples will be collected at planned time points to evaluate vaccine-induced T-cell and B-cell responses using assays such as IFNγ ELISpot, flow cytometry, single-cell RNA sequencing, TCR sequencing, and BCR sequencing.

Preliminary clinical activity will be assessed by disease-free survival, imaging, tumor markers such as CA125 and HE4, and circulating tumor DNA testing for minimal residual disease.

Feasibility will be evaluated by vaccine production and release time, cold-chain delivery, treatment completion rate, and coordination with chemotherapy and other adjuvant treatments.

\*\*Sample Size and Statistical Analysis\*\*

The planned sample size is 9 to 18 participants, based on the 3+3 dose-escalation design. This Phase I study is not designed to test treatment superiority or non-inferiority. Safety, tolerability, immune response, disease-free survival, minimal residual disease clearance, and feasibility outcomes will mainly be summarized descriptively.

All participants who receive at least one vaccine dose will be included in the safety analysis. Immune and clinical outcomes will be analyzed in the relevant evaluable populations. Kaplan-Meier methods may be used to describe disease-free survival, and exploratory statistical methods may be used to evaluate associations between immune responses and clinical outcomes.

Participants will be followed after treatment to record survival status and long-term adverse events until death, study closure, or the end of follow-up, whichever occurs first.

Вмешательства

• Препарат Low Dose
  Participants will receive the NeoOVSV mRNA-lipid nanoparticle vaccine at a dose of 25 μg, corresponding to an approximate injection volume of 0.2 mL, administered by intramuscular injection. Vaccination will start approximately 4 weeks after surgery. The vaccine schedule includes 6 priming doses given once every 3 weeks during adjuvant chemotherapy, followed by 3 booster doses given once weekly after chemotherapy. Standard adjuvant chemotherapy will also start approximately 4 weeks after surgery
• Препарат middle dose
  Participants will receive the NeoOVSV mRNA-lipid nanoparticle vaccine at a dose of 50 μg, corresponding to an approximate injection volume of 0.4 mL, administered by intramuscular injection. Vaccination will start approximately 4 weeks after surgery. The vaccine schedule includes 6 priming doses given once every 3 weeks during adjuvant chemotherapy, followed by 3 booster doses given once weekly after chemotherapy. Standard adjuvant chemotherapy will also start approximately 4 weeks after surgery
• Препарат high dose
  Participants will receive the NeoOVSV mRNA-lipid nanoparticle vaccine at a dose of 100 μg, corresponding to an approximate injection volume of 0.8 mL, administered by intramuscular injection. Vaccination will start approximately 4 weeks after surgery. The vaccine schedule includes 6 priming doses given once every 3 weeks during adjuvant chemotherapy, followed by 3 booster doses given once weekly after chemotherapy. Standard adjuvant chemotherapy will also start approximately 4 weeks after surger

Первичные конечные точки

• safety assessment [Срок оценки: Throughout treatment, followed up to 18 months after treatment]

Вторичные конечные точки (4)

• Disease-Free Survival (DFS) [Срок оценки: From surgery date up to 24 months post-surgery; assessed every 3 months until recurrence, death, or end of follow-up.]
• Immunogenicity assessment [Срок оценки: Baseline preoperatively; 1 week after the third priming dose of the vaccine; 1 week after completion of the priming phase; 1 week after the first booster dose; and 6 months of follow-up.]
• 12-month and 24-month DFS rates [Срок оценки: At 12 months and 24 months post-surgery (fixed time points).]
• Minimal Residual Disease (MRD) Clearance [Срок оценки: Pre-operatively (baseline); 1 week after the third priming dose; 1 week after completion of the priming phase; 1 week after the first booster dose; and at 6-month follow-up (5 fixed time points).]

Критерии участия

Критерии включения

• 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 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07724106 · 2026(862)

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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