Purpose: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are expected to be synergistic with intraperitoneal (IP) immunotherapy by increasing tumor antigen expression and mutational load. We assessed the feasibility and safety of IP nivolumab following complete CRS and HIPEC in pretreated patients with recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT03959761). Patients and Methods: Patients received IP nivolumab (0.5, 1 and 3 mg/kg) using a 3+3 dose-escalation design, starting 5-7 days after CRS and HIPEC. Four IP Q2W nivolumab infusions were planned. The primary objective was to demonstrate the feasibility of IP nivolumab based on dose-limiting toxicity (DLT). Secondary objectives were to assess changes in tolerance of CRS and HIPEC. Results: A total of 17 patients were enrolled including 10 patients in the dose-escalation and 7 patients in the expansion phase. No DLT was observed at any dose-level in the 9 evaluable patients. Six of the 17 patients (35%) did not complete all planned infusions: 4 (23.5%) due to peritoneal catheter complications, 2 (11.8%) due to early progression. No procedure-related deaths occurred. Eleven patients (65%) experienced serious adverse events (SAEs), mainly transitory grade 3-4 transaminases elevations (6/11), and surgery-related (9/11). Four SAEs were related to the peritoneal catheter and two to HIPEC. No SAEs/grade 3-4 adverse events related to IP nivolumab occurred. Conclusions: This is the first study demonstrating the feasibility of IP nivolumab in patients with relapsed advanced ovarian cancer; further investigation at 3 mg/kg is warranted.

中文翻译：

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晚期卵巢癌减瘤手术和腹腔热化疗后腹腔内纳武利尤单抗：一项扩大队列的 I 期研究


目的：细胞减灭手术（CRS）和腹腔热灌注化疗（HIPEC）有望通过增加肿瘤抗原表达和突变负荷与腹腔内（IP）免疫疗法产生协同作用。我们在接受过治疗的复发性卵巢癌患者中评估了完全 CRS 和 HIPEC 后 IP nivolumab 的可行性和安全性（ClinicalTrials.gov 标识符：NCT03959761）。患者和方法：患者采用 3+3 剂量递增设计，在 CRS 和 HIPEC 后 5-7 天开始接受 IP nivolumab（0.5、1 和 3 mg/kg）。计划进行四次 Q2W 纳武单抗 IP 输注。主要目的是证明基于剂量限制毒性 (DLT) 的 IP nivolumab 的可行性。次要目标是评估 CRS 和 HIPEC 耐受性的变化。结果：共有 17 名患者入组，其中剂量递增期 10 名患者，扩展期 7 名患者。在 9 名可评估的患者中，在任何剂量水平下均未观察到 DLT。 17 名患者中有 6 名 (35%) 未完成所有计划输注：4 名 (23.5%) 因腹膜导管并发症，2 名 (11.8%) 因早期进展。没有发生与手术相关的死亡。 11 名患者 (65%) 经历了严重不良事件 (SAE)，主要是暂时性 3-4 级转氨酶升高 (6/11) 和手术相关 (9/11)。 4 例 SAE 与腹膜导管相关，2 例与 HIPEC 相关。未发生与 IP nivolumab 相关的 SAE/3-4 级不良事件。结论：这是第一项证明IP纳武单抗治疗复发性晚期卵巢癌患者可行性的研究；有必要对 3 mg/kg 进行进一步研究。