Clinical First-in-human Dose Escalation Study Evaluating the Safety and Tolerability of Intravenous Administration of a Tetravalent RNA-lipoplex Cancer Vaccine Targeting the Tumor-associated Antigens NY-ESO-1, Tyrosinase, MAGE-A3, and TPTE in Patients With Advanced Melanoma
概览
- 阶段
- 1 期
- 干预措施
- Lipo-MERIT
- 疾病 / 适应症
- Melanoma
- 发起方
- BioNTech SE
- 入组人数
- 119
- 试验地点
- 4
- 主要终点
- Number of Adverse Events as a Measure of safety and tolerability
- 状态
- 已完成
- 最后更新
- 上个月
概览
简要总结
The purpose of this study is to determine the safety and tolerability of intravenous administration of a tetravalent RNA-lipoplex cancer vaccine targeting four tumor-associated antigens in patients with advanced melanoma.
详细描述
* The Lipo-MERIT vaccine consists of four naked ribonucleic acid (RNA)-drug products (DPs) that are optimized to induce antigen-specific cluster of differentiation (CD)8+ and CD4+ T cell responses against the four selected malignant melanoma-associated antigens New York-ESO 1 (NY-ESO-1), tyrosinase, Melanoma-associated antigen A3 (MAGE-A3), and Trans-membrane phosphatase with tensin homology (TPTE). * In this study, naked RNA DPs were formulated with liposomes to form RNA-lipoplexes (RNA-LPX) that (i) protect RNA from degradation in the serum, (ii) enable in vivo targeting of antigen-presenting cells (APC), and therefore (iii) constitute a novel vaccine formulation that supports intravenous administration. As of August 31, 2021 the RNA-DPs RBL001.1, RBL002.2, RBL003.1 and RBL004.1 initially used for treatment have been replaced by the improved RNA drug substances RBL001.3, RBL002.4, RBL003.3 and RBL004.3. These drug substances are formulated in lipoplexes to yield RNA-LPX (drug product). The added maximum duration of trial treatment with the new drug products is 18 months. * The Lipo-MERIT vaccine is expected to lead to several effects contributing to its immunological (therapeutic) effect. First, the RNA-LPX home to APCs in lymphoid organs after intravenous injection, where they are rapidly taken up by professional APCs. Incorporated RNA is translocated to the cytoplasm leading to its translation by the host ribosome complex into four Antigen encoding proteins which are processed and presented on both Human leukocyte antigen (HLA)-class I as well as HLA-class II molecules. Consecutively, antigen-specific CD8+ and CD4+ T cell responses will be triggered by HLA-peptide complexes on the surface of antigen-presenting cells. * In addition, the Lipo-MERIT vaccine is expected to transiently activate APCs (change of surface marker expression and cytokine secretion) via signaling of Toll-like receptor (TLR)s, subsequently leading to the transient induction of inflammatory cytokines (such as Interferon (IFN)-α and Interferon gamma induced protein 10 \[IP-10\]) supporting the induction of tumor-antigen specific T cell responses.
研究者
入排标准
入选标准
- •Cohort I: stage IV malignant melanoma (American joint committee on cancer (AJCC) 2009 melanoma classification)
- •Cohorts II-VII and expanded cohorts: stage IIIB-C, or stage IV of malignant melanoma (AJCC 2009 melanoma classification) \[only applicable until approval of protocol version 10.0\] Expanded cohort C only patients with stage IV melanoma (AJCC 2009 melanoma classification) with measurable disease (at least one target lesion according irRECIST) \[applicable for all patients included after approval of protocol version 10.0 and higher\] and with disease progression at the time of first treatment with Investigational medicinal product (IMP) \[applicable for all patients included after approval of protocol version 11.0\]
- •Therapy only for subjects not eligible or declining any other available approved therapy after all available treatment options have been transparently disclosed (to be documented!)
- •Expression of either NY-ESO-1, tyrosinase, MAGE-A3, and/or TPTE confirmed by RT-qPCR analysis from formalin-fixed paraffin-embedded (FFPE)
- •≥ 18 years of age
- •Written informed consent
- •Eastern cooperative oncology group (ECOG) performance status (PS) 0-1
- •Life expectancy ≥ 6 months
- •White blood cell (WBC) ≥ 3x10\^9/L
- •Hemoglobin ≥ 9 g/dL
排除标准
- •Pregnancy or breastfeeding
- •Primary ocular melanoma
- •Concurrence of a second malignancy other than squamous or basal cell carcinoma, non-active prostate cancer, or cervical carcinoma in situ or non-active treated urothelial carcinoma
- •Brain metastases
- •Patients with history of treated or inactive brain metastasis are eligible for treatment in expanded cohort C, provided they meet all of the following criteria:
- •measurable disease outside of the brain (in addition to inactive brain metastasis);
- •no ongoing requirement of corticosteroids as therapy for brain metastases,
- •with corticosteroids discontinued ≥1 week prior to visit 2 (day 1) with no ongoing symptoms attributable to brain metastasis;
- •the screening brain radiographic imaging is ≥ 4 weeks since completion of radiotherapy
- •Post-splenectomy Patients
研究组 & 干预措施
Lipo-MERIT
7 dose escalation cohorts (3 +3 design) and 3 expanded cohorts
干预措施: Lipo-MERIT
结局指标
主要结局
Number of Adverse Events as a Measure of safety and tolerability
时间窗: up to 8 years
Number of patients with adverse events, total number of adverse events, dose limiting toxicities
次要结局
- Overall survival (OS)(up to 8 years)
- Objective response rate (ORR)(up to 8 years)
- Duration of response (DoR)(up to 8 years)
- Disease control rate (DCR)(up to 8 years)
- Progression Free Survival (PFS)(up to 8 years)
- Change of induced T-cell responses for Lipo-MERIT vaccine from visit 2 (day 1) to day 71 (assessed by immunoassays)(up to 8 years)