VALTIVE1 研究方案：一项验证 Tie2 作为首个血管生成抑制剂肿瘤血管反应生物标志物的研究。

The VALTIVE1 study protocol: a study for the validation of Tie2 as the first tumour vascular response biomarker for VEGF inhibitors.

机构信息

Centre for Trials Research, Cardiff University, 6thFloor, Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK.

The University of Manchester, The Christie NHS Foundation Trust, Manchester, UK.

出版信息

BMC Cancer. 2024 Oct 24;24(1):1309. doi: 10.1186/s12885-024-13073-0.

DOI:10.1186/s12885-024-13073-0

PMID:39448911

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11515440/

Abstract

BACKGROUND

Anti-angiogenic, VEGF inhibitors (VEGFi) increase progression-free survival (PFS) and, in some cases, overall survival in many solid tumours. However, their use has been compromised by a lack of informative biomarkers. We have shown that plasma Tie2 is the first tumour vascular response biomarker for VEGFi in ovarian, colorectal and gall bladder cancer: If plasma Tie2 concentrations do not change after 9 weeks of treatment with a VEGFi, the patient does not benefit, whereas a confirmed reduction of at least 10% plasma Tie2 defines a vascular response with a hazard ratio (HR) for PFS of 0.56. The aim of the VALTIVE1 study is to validate the utility of plasma Tie2 as a vascular response biomarker and to optimise the Tie2-definition of vascular response so that the subsequent randomised discontinuation VALTIVE2 study can be powered optimally.

METHODS

VALTIVE1 is a multi-centre, single arm, non-interventional biomarker study, with a sample size of 205 participants (176 bevacizumab-treated participants + 29 participants receiving bevacizumab and olaparib/PARPi), who are 16 years or older, have FIGO stage IIIc/IV ovarian cancer on treatment with first-line platinum-based chemotherapy and bevacizumab. Their blood plasma samples will be collected before, during, and after treatment and the concentration of Tie2 will be determined. The primary objective is to define the PFS difference between Tie2-defined vascular responders and Tie2-defined vascular non-responders in patients receiving bevacizumab for high-risk Ovarian Cancer. Secondary objectives include defining the relationship between Tie2-defined vascular progression and disease progression assessed according to RECIST 1.1 criteria and assessing the impact of PARPi on the plasma concentration of Tie2 and, therefore, the decision-making utility of Tie2 as a vascular response biomarker for bevacizumab during combined bevacizumab-PARPi maintenance.

DISCUSSION

There is an urgent need to establish a test that tells patients and their doctors when VEGFi are working and when they stop working. The data generated from this study will be used to design a second trial aiming to prove conclusively the value of the Tie2 test.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT04523116. Registered on 21 Aug 2020.

摘要

背景

抗血管生成、VEGF 抑制剂（VEGFi）可增加许多实体瘤患者的无进展生存期（PFS），在某些情况下还可增加总生存期。然而，由于缺乏有意义的生物标志物，其应用受到了限制。我们已经表明，血浆 Tie2 是卵巢癌、结直肠癌和胆囊癌中 VEGFi 的首个肿瘤血管反应生物标志物：如果患者在接受 VEGFi 治疗 9 周后血浆 Tie2 浓度没有变化，则表明患者无法从中获益，而确认至少降低 10%的血浆 Tie2 则定义了血管反应，其 PFS 的风险比（HR）为 0.56。VALTIVE1 研究的目的是验证血浆 Tie2 作为血管反应生物标志物的实用性，并优化 Tie2 定义的血管反应，以便随后进行随机停药的 VALTIVE2 研究能够得到最佳的动力。

方法

VALTIVE1 是一项多中心、单臂、非干预性的生物标志物研究，样本量为 205 名参与者（176 名接受贝伐珠单抗治疗的参与者+29 名接受贝伐珠单抗和奥拉帕利/PARPi 治疗的参与者），年龄在 16 岁及以上，FIGO 分期为 IIIc/IV 期卵巢癌，正在接受一线含铂化疗和贝伐珠单抗治疗。他们的血浆样本将在治疗前、治疗中和治疗后采集，并测定 Tie2 的浓度。主要目的是确定在接受贝伐珠单抗治疗的高危卵巢癌患者中，Tie2 定义的血管反应者与 Tie2 定义的血管无反应者之间的 PFS 差异。次要目标包括确定根据 RECIST 1.1 标准评估的 Tie2 定义的血管进展与疾病进展之间的关系，并评估 PARPi 对 Tie2 血浆浓度的影响，从而评估 Tie2 作为贝伐珠单抗联合 PARPi 维持治疗中血管反应生物标志物的决策实用性。