A Phase I Clinical Trial of Personalized Neoantigen Peptide Vaccine in Combination With Pembrolizumab for the Safety and Efficacy in Patients With Advanced, Recurrent or Refractory Renal Cell Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Incidence and severity of treatment-emergent adverse events (TEAE)
研究概览
简要总结
This is a Phase I, single-center, open-label, single-arm clinical trial to evaluate the safety and efficacy of personalized neoantigen polyepitope peptide vaccine combined with pembrolizumab in patients with advanced, recurrent or refractory renal cell carcinoma (RCC).
Background: Renal cell carcinoma is one of the most common malignancies of the urinary system. Although pembrolizumab has become a standard first-line treatment, the objective response rate (ORR) of monotherapy is only 20-40%, and most patients eventually develop primary or acquired resistance. Tumor neoantigens are specific antigens produced by tumor-specific gene mutations, with high immunogenicity and tumor specificity, making them ideal targets for tumor immunotherapy. Preliminary clinical studies have shown that neoantigen vaccines can produce synergistic effects when combined with pembrolizumab.
Study Design: This is an investigator-initiated trial (IIT) conducted at Peking University First Hospital. The study will enroll 5-8 patients in two stages: an initial safety assessment cohort (3 patients) followed by an expansion cohort (5 additional patients) if safety criteria are met. The study drug is a personalized neoantigen polyepitope peptide vaccine (Neo-RCC), produced by Mingzhibenyuan Medical Technology (Beijing) Co., Ltd., based on whole exome sequencing (WES) and transcriptome sequencing (RNA-seq) of each patient's tumor tissue. The vaccine is administered via subcutaneous injection in combination with Polyinosinic-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose (Poly-ICLC) adjuvant, with a priming phase (5 injections on Days 0, 3, 7, 14, 21) and a boosting phase (3 injections on Weeks 6, 12, and 20), totaling 8 injections. Pembrolizumab (200 mg intravenous [IV] every 3 weeks [Q3W]) is administered concurrently as combination therapy.
Primary Objective: To evaluate the safety of the personalized neoantigen peptide vaccine in advanced RCC patients, as measured by the incidence and severity of treatment-emergent adverse events (TEAE) graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Secondary Objectives: To evaluate pharmacokinetic characteristics; to assess efficacy including objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Key Eligibility Criteria: Adults (≥18 years) with Stage III or IV, locally advanced, recurrent or metastatic non-surgical RCC who have achieved disease stability for ≥3 months after prior targeted therapy combined with pembrolizumab; measurable disease per RECIST v1.1; Eastern Cooperative Oncology Group (ECOG) performance status 0-3; adequate organ function; and ≥50 tumor gene mutations detectable from biopsy tissue.
Safety Monitoring: A Data Safety Monitoring Board (DSMB) will oversee patient safety. Dose-limiting toxicities (DLT) are defined according to protocol-specified criteria. If ≥2 DLTs occur in the initial cohort, the adjuvant dose will be reduced by 50% and the study will proceed with a de-escalation cohort.
详细描述
Study Rationale: This study addresses the unmet need for effective second-line or later treatment options for advanced renal cell carcinoma (RCC) patients who have progressed or become refractory after initial immunotherapy. The combination strategy leverages the complementary mechanisms of personalized neoantigen vaccines (which activate tumor-specific T-cell responses) and pembrolizumab (which blocks programmed cell death protein 1 (PD-1)-mediated immune suppression), potentially overcoming PD-1 inhibitor resistance.
Neoantigen Prediction and Vaccine Manufacturing: Tumor tissue and peripheral blood samples are collected for whole exome sequencing (WES) and RNA sequencing (RNA-seq). A proprietary neoantigen prediction platform (neoTrue AI) analyzes sequencing data to identify tumor-specific mutations and predict neoantigen-major histocompatibility complex (MHC) binding affinity. The top 10-30 ranked neoantigen peptides are selected for Good Manufacturing Practice (GMP)-grade synthesis. The median manufacturing period is approximately 12 weeks. Each peptide is 300 μg, mixed with Polyinosinic-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose (Poly-ICLC) adjuvant (0.5 mg per pool), and administered as 4 pools (left/right axilla and left/right groin) in 250 μL per injection site.
Pembrolizumab Administration: Pembrolizumab 200 mg is administered intravenously (IV) every 3 weeks (Q3W), diluted in 100 mL 0.9% sodium chloride over 30 minutes. Treatment continues for up to 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. During the vaccine manufacturing period (~12 weeks), pembrolizumab may be continued as bridging therapy to maintain disease stability.
Dose-Limiting Toxicity (DLT) Definition: Hematologic: Grade 4 neutropenia (absolute neutrophil count [ANC] <0.5×10⁹/L) lasting >7 days; Grade 4 thrombocytopenia (<25×10⁹/L) within 7 days. Non-hematologic: Grade 3 non-hematologic toxicity lasting >7 days (with specified exceptions); Grade 4 toxicity. Immune-related: ≥Grade 3 immune pneumonitis, colitis, hepatitis; any-grade myocarditis; ≥Grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) or immune encephalitis; ≥Grade 3 severe skin reactions (Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN], drug reaction with eosinophilia and systemic symptoms [DRESS]). Other: ≥Grade 2 cytokine release syndrome (CRS) (per American Society for Transplantation and Cellular Therapy [ASTCT] criteria); ≥Grade 3 injection-site reactions requiring surgical intervention; ≥Grade 3 allergic reactions; ≥Grade 3 infections; ≥Grade 3 thromboembolic events; ≥Grade 3 bleeding.
DLT Management: If ≥2 DLTs occur in the first 3 patients during the first 8 weeks (D0-D56), the adjuvant total dose will be reduced by 50% (to 1.0 mg), and 2 additional patients will be enrolled in the de-escalation cohort. If ≥2 DLTs occur in the de-escalation cohort, the study will be terminated. If ≥3 DLTs occur in the expansion cohort, the regimen will be deemed to have unacceptable toxicity.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed Stage III or IV, locally advanced, recurrent or metastatic renal cell carcinoma (RCC) not amenable to curative surgery
- •Disease stability for ≥3 months after prior single pembrolizumab therapy, with documented progression or intolerance to standard treatment
- •At least one measurable lesion per RECIST v1.1 (longest diameter ≥10 mm for non-lymph node lesions; short axis ≥15 mm for lymph nodes; or bone lesions confirmed by CT/MRI)
- •Age ≥18 years
- •Estimated life expectancy ≥3 months
- •ECOG performance status 0-3
- •Availability of tumor tissue (biopsy or archival specimen) for whole exome sequencing (WES) and RNA sequencing (RNA-seq), with ≥50 tumor gene mutations detectable
- •Adequate organ function as defined by laboratory parameters within 14 days prior to enrollment:
- •8.1 Hematologic: Absolute Neutrophil Count(ANC) ≥1.5×10⁹/L, platelet count ≥100×10⁹/L, hemoglobin ≥90 g/L; 8.2 Hepatic: total bilirubin(TBIL) ≤1.5×Upper Limit of Normal(ULN), Aspartate Aminotransferase(AST)/Alanine Aminotransferase(ALT) ≤2.5×ULN (≤5×ULN if liver metastases present); 8.3 Renal: serum creatinine ≤1.5×ULN or creatinine clearance ≥50 mL/min (Cockcroft-Gault formula); 8.4 Coagulation: international normalized ratio(INR) ≤1.5, activated partial thromboplastin time(APTT) ≤1.5×ULN; 8.5 Cardiac: Left Ventricular Ejection Fractions(LVEF) ≥50% by echocardiography;
- •Ability to comply with study procedures and follow-up schedule;
- •Signed informed consent form;
- •For women of childbearing potential: negative serum pregnancy test (Human Chorionic Gonadotropin sensitivity ≤25 IU/L) within 7 days prior to enrollment; agreement to use effective contraception during study and for 4 weeks after last dose;
- •For men: agreement to use effective contraception during study and for 4 weeks after last dose.
排除标准
- •Pregnant or lactating women
- •Prior treatment with:
- •2.1 Two or more lines of immune checkpoint inhibitor (ICI) systemic therapy; 2.2 CTLA-4 inhibitor (e.g., ipilimumab); 2.3 Tumor vaccine therapy (including neoantigen vaccine, dendritic cell vaccine, etc.); 2.4 Chemotherapy specifically for renal cell carcinoma; 2.5 Allogeneic hematopoietic stem cell or solid organ transplantation;
- •Active autoimmune disease or other immune-mediated disorders requiring systemic immunosuppressive therapy;
- •Participation in another investigational drug study within 4 weeks prior to first dose;
- •Active infection including:
- •5.1 Known Human Immunodeficiency Virus(HIV) infection; 5.2 Active hepatitis B (HBsAg positive and Hepatitis B Virus-DNA >500 IU/mL) or hepatitis C (HCV-RNA positive); 5.3 Active tuberculosis (T-SPOT or PPD positive with clinical symptoms, or chest CT suggestive of active TB); 5.4 Severe infection requiring intravenous antibiotics within 2 weeks prior to enrollment, or uncontrolled systemic infection;
- •Symptomatic central nervous system (CNS) metastases; exception: patients with treated CNS metastases stable for ≥4 weeks without neurological symptoms and without corticosteroid requirement;
- •Uncontrolled comorbidities including:
- •7.1 Symptomatic congestive heart failure (New York Heart Association Class III-IV); 7.2 Unstable angina or myocardial infarction within 6 months; 7.3 Uncontrolled arrhythmia; 7.4 Uncontrolled hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg despite standard treatment); 7.5 Active peptic ulcer or gastrointestinal bleeding; 7.6 Active interstitial lung disease or pulmonary fibrosis;
- •Other malignancy within 5 years (except cured cervical carcinoma in situ, basal cell carcinoma, or squamous cell skin carcinoma);
- •Live vaccine administration within 4 weeks prior to enrollment or planned during study (inactivated vaccines allowed);
- •Known hypersensitivity to peptide vaccine components, adjuvants (e.g., Montanide ISA-51, Poly-ICLC), or pembrolizumab;
- •Sarcomatoid or rhabdoid RCC as predominant histology (mixed histology allowed if non-pure sarcomatoid/rhabdoid);
- •Any condition that, in the investigator's opinion, would compromise patient safety or compliance;
- •Any other condition that the investigator considers unsuitable for study participation.
结局指标
主要结局
Incidence and severity of treatment-emergent adverse events (TEAE)
时间窗: From first dose of study drug through 30 days after last dose, approximately 24 weeks
The primary safety endpoint is the incidence and severity of treatment-emergent adverse events (TEAE), graded according to NCI CTCAE v5.0. TEAE is defined as any adverse event that occurs from the first administration of the study drug through 30 days after the last dose, or before initiation of new anti-tumor therapy, whichever occurs first. Key assessments include: (1) overall TEAE incidence rate; (2) Grade ≥3 TEAE incidence rate; (3) serious adverse event (SAE) incidence rate; (4) adverse events of special interest (AESI) including immune-related adverse events (irAEs), injection-site reactions, and cytokine release syndrome; (5) TEAE leading to dose modification, interruption, or permanent discontinuation; (6) treatment-related death. Safety monitoring covers the screening period, treatment period (8 vaccine injections over \~20 weeks plus concurrent pembrolizumab), and follow-up period.
次要结局
- Objective Response Rate (ORR) per RECIST v1.1(From first dose through disease progression or death, up to 2 years)
- Duration of Response (DOR) per RECIST v1.1(From first documented response to disease progression or death, up to 2 years)
- Disease Control Rate (DCR) per RECIST v1.1(From first dose through 6 weeks after first dose, up to 2 years)
- Progression-Free Survival (PFS) per RECIST v1.1(From first dose to disease progression or death, up to 2 years)
- Overall Survival (OS)(From first dose to death or last contact, up to 2 years)
- Cmax of neoantigen-specific T-cell response(From first dose through 30 days after last dose, approximately 24 weeks)
- Tmax of neoantigen-specific T-cell response(From first dose through 30 days after last dose, approximately 24 weeks)
- Duration of neoantigen-specific T-cell response(From first dose through 30 days after last dose, approximately 24 weeks)
- Area under curve(AUC) of neoantigen-specific T-cell response(From first dose through 30 days after last dose, approximately 24 weeks)
- Percent change from baseline in neoantigen-specific T-cell response(From first dose through 30 days after last dose, approximately 24 weeks)
研究者
Jian Lin
Principal Investigator, Clinical Professor
Peking University First Hospital