Department of Gynaecology with Center for Oncological Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
Department of Gynaecology and Obstetrics TU Dresden and National Center for Tumor Diseases (NCT/UCC), Dresden, Germany.
J Cancer Res Clin Oncol. 2023 Aug;149(10):7637-7649. doi: 10.1007/s00432-023-04647-9. Epub 2023 Mar 31.
Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC).
Patients (≥ 18 years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4 mg/m (day 1, 8, 15, ever 28 days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400 mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT01600573.
Between June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400 mg/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3-4 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5 months (95% CI 2.0-5.0). Due to early progression only 20% of the patients were able to start with maintenance treatment.
The combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit.
帕唑帕尼在实体瘤中具有有前景的抗血管生成活性。这项由研究者发起的 I/II 期试验评估了拓扑替康联合帕唑帕尼在铂耐药或中敏感复发性卵巢癌（ROC）中的疗效。
本多中心、开放标签试验纳入了首次或第二次复发的年龄≥18 岁的患者。I 期分析拓扑替康 4mg/m2（第 1、8、15 天，每 28 天一次）6 个周期，以确定帕唑帕尼的最大耐受剂量（MTD），采用 400mg 的起始剂量进行剂量递增方案。II 期分析安全性和疗效方面。所有有临床缓解的患者均允许使用帕唑帕尼维持治疗，直至疾病进展。本试验在 ClinicalTrials.gov 注册，编号为 NCT01600573。
2012 年 6 月至 2017 年 2 月，11 例患者入组 I 期，50 例患者入组 II 期研究。帕唑帕尼的 MTD 确定为 400mg/天。血液学和肝毒性导致剂量限制性毒性（DLT）和最常见的 3-4 级不良事件：白细胞减少（25%）、中性粒细胞减少（22%）、血小板减少（19%）、胆汁淤积（20%）和肝细胞损伤（15%），这些毒性常导致剂量调整，但没有新的危及生命的事件。总体缓解率为 16%，临床获益率为 68%。中位无进展生存期（PFS）为 3.5 个月（95%CI 2.0-5.0）。由于早期进展，只有 20%的患者能够开始维持治疗。
帕唑帕尼联合每周拓扑替康是可行的，导致可管理的血液学和肝毒性，但尽管缓解率令人鼓舞，与生存获益无关。
