Phase I and II Clinical Studies of the STING Agonist Ulevostinag with and without Pembrolizumab in Participants with Advanced or Metastatic Solid Tumors or Lymphomas.

patients_and_methods

In a phase I study (NCT03010176) with an accelerated titration design/modified toxicity probability interval method, participants with advanced/metastatic solid tumors or lymphomas received intratumoral ulevostinag (±intravenous pembrolizumab).

在一项采用加速剂量递增设计/改良毒性概率区间方法的I期研究（NCT03010176）中，患有晚期或转移性实体瘤或淋巴瘤的参与者接受了瘤内ulevostinag治疗（±静脉注射pembrolizumab）。

In an expansion phase, participants with head and neck squamous cell carcinoma (HNSCC) or triple-negative breast cancer received the combination.

在扩展阶段，头颈部鳞状细胞癌（HNSCC）或三阴性乳腺癌的参与者接受了联合治疗。

Primary objectives were safety/tolerability and identifying the recommended phase II dose; biomarkers were exploratory.

主要目标是安全性和耐受性，以及确定推荐的二期剂量；生物标志物是探索性的。

In a randomized phase II study (NCT04220866), participants with untreated metastatic or unresectable, recurrent HNSCC received intravenous pembrolizumab (±ulevostinag 540 µg).

在一项随机II期研究(NCT04220866)中，未接受治疗的转移性或不可切除的复发性头颈部鳞状细胞癌(HNSCC)患者接受了静脉注射的帕博利珠单抗（±乌列司他540微克）。

The primary objective was antitumor activity.

主要研究目的是抗肿瘤活性。

Pembrolizumab 200 mg was administered every 3 weeks in both studies.

在两项研究中，每3周给予200 mg的帕博利珠单抗。

Results

In the phase I study (NCT03010176; N = 156), the most common adverse eventwas pyrexia (70%).

在I期研究(NCT03010176; N=156)中，最常见的不良事件是发热(70%)。

Plasma ulevostinag concentrations increased dose-dependently.

血浆中ulevostinag的浓度呈剂量依赖性增加。

Circulating levels of C-X-C motif chemokine 10, IFNγ, and IL-6 showed elevation at 2 to 4 hours, peak at 6 to 8 hours, and plateau/partial resolution at 24 hours but, beyond the 540 µg dose, did not show a clear dose-effect relationship.

循环中的C-X-C基序趋化因子10、干扰素γ和白细胞介素6水平在2至4小时升高，在6至8小时达到峰值，并在24小时时达到平台期/部分解决，但在超过540微克剂量后，没有显示出明确的剂量-效应关系。

Ten participants experienced dose-limiting toxicities; the recommended phase II dose for intratumoral ulevostinag was 540 µg.

十名参与者经历了剂量限制性毒性；推荐的 II 期剂量为肿瘤内注射的 ulevostinag 为 540 微克。

In the phase II study (NCT04220866), 4 of 8 participants treated with combination therapy and 1 of 10 treated with pembrolizumab monotherapy had a complete or partial response.

在 II 期研究（NCT04220866）中，接受联合治疗的 8 名参与者中有 4 名，以及接受 pembrolizumab 单药治疗的 10 名参与者中有 1 名，实现了完全或部分缓解。

The most common adverse eventwas pyrexia (n = 5).

最常见的不良事件是发热（n = 5）

Conclusions

Intratumoral ulevostinag (±pembrolizumab) had manageable toxicity, dose-dependent pharmacokinetics, and evidence of STING activation and target engagement.

肿瘤内注射的ulevostinag（±pembrolizumab）具有可管理的毒性，剂量依赖的药代动力学，并有STING激活和靶点结合的证据。

Combination therapy showed antitumor activity in participants with untreated metastatic or unresectable, recurrent HNSCC.

联合治疗在未接受治疗的转移性或不可切除的复发性头颈部鳞状细胞癌患者中显示出抗肿瘤活性。