Spiegelberg Linda, Houben Ruud, Niemans Raymon, de Ruysscher Dirk, Yaromina Ala, Theys Jan, Guise Christopher P, Smaill Jeffrey B, Patterson Adam V, Lambin Philippe, Dubois Ludwig J
Department of Precision Medicine, The M-Lab, GROW - School for Oncology and Developmental Biology, Maastricht Comprehensive Cancer Centre, Maastricht University Medical Centre, Maastricht, The Netherlands.
Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
Clin Transl Radiat Oncol. 2019 Jan 18;15:62-69. doi: 10.1016/j.ctro.2019.01.005. eCollection 2019 Feb.
Hypoxia-activated prodrugs (HAPs) are designed to specifically target the hypoxic cells of tumors, which are an important cause of treatment resistance to conventional therapies. Despite promising preclinical and clinical phase I and II results, the most important of which are described in this review, the implementation of hypoxia-activated prodrugs in the clinic has, so far, not been successful. The lack of stratification of patients based on tumor hypoxia status, which can vary widely, is sufficient to account for the failure of phase III trials. To fully exploit the potential of hypoxia-activated prodrugs, hypoxia stratification of patients is needed. Here, we propose a biomarker-stratified enriched Phase III study design in which only biomarker-positive (i.e. hypoxia-positive) patients are randomized between standard treatment and the combination of standard treatment with a hypoxia-activated prodrug. This implies the necessity of a Phase II study in which the biomarker or a combination of biomarkers will be evaluated. The total number of patients needed for both clinical studies will be far lower than in currently used randomize-all designs. In addition, we elaborate on the improvements in HAP design that are feasible to increase the treatment success rates.
缺氧激活前体药物（HAPs）旨在特异性靶向肿瘤的缺氧细胞，而缺氧细胞是传统疗法治疗耐药的重要原因。尽管临床前以及临床I期和II期试验取得了令人鼓舞的结果（本综述将介绍其中最重要的结果），但迄今为止，缺氧激活前体药物在临床上的应用尚未成功。由于患者未根据肿瘤缺氧状态进行分层（肿瘤缺氧状态差异很大），这足以解释III期试验的失败。为了充分发挥缺氧激活前体药物的潜力，需要对患者进行缺氧分层。在此，我们提出一种生物标志物分层富集III期研究设计，即仅将生物标志物阳性（即缺氧阳性）的患者在标准治疗与标准治疗联合缺氧激活前体药物之间进行随机分组。这意味着有必要开展一项II期研究，对生物标志物或生物标志物组合进行评估。这两项临床研究所需的患者总数将远低于目前使用的全随机设计。此外，我们详细阐述了HAP设计方面可行的改进措施，以提高治疗成功率。
