靶向VEGF和HGF的首個DARPin 候選藥物MP0250在晚期實體腫瘤患者中的第一期人體研究

First-in-Human Phase I Study of MP0250, a First-in-Class DARP in Drug Candidate TargetingVEGF and HGF, in Patients With Advanced Solid Tumors（J Clin Oncol;IF：32.956）

BAIRD R D, LINOSSI C, MIDDLETON M, et al. First-in-Human Phase I Study of MP0250, a First-in-Class DARPin Drug Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors [J]. J Clin Oncol, 2020, Jco2000596.

PURPOSE 目的

A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment.

對DARPin候選藥物MP0250進行了首次人體研究。MP0250特異性地抑制血管內皮生長因子(VEGF)和肝細胞生長因子(HGF)，目的是破壞腫瘤微環境。

PATIENTS AND METHODS 患者及方法

A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the doseescalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n =13, 8 mg/kg, once every 2 weeks and n =8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts.

對45例晚期實體腫瘤患者進行了一項多中心、開放、重複給藥的I期研究，以評估MP0250的安全性、耐受性和藥代動力學。在劑量遞增部分，24例患者接受5種不同劑量(0.5~12 mg/kg)的MP0250靜脈滴注，每2周1次，每次3h。在確定最大耐受量(MTD)後，21例患者在劑量確認佇列中給予MP0250 1h靜脈滴注(n=13，8 mg/kg，每2周1次；n=8，12 mg/kg，每3周1次)。

RESULTS 結果

In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks.

在劑量遞增佇列中，每兩週接受一次12毫克/公斤MP0250治療的患者出現劑量限制性毒性。因此，MTD為8 mg/kg，每2周1次，或12 mg/kg，每3周1次。最常見的不良事件是高血壓(69%)、蛋白尿(51%)、腹瀉和噁心(均為36%)；24%的患者報告有低蛋白血癥。大多數AEs與VEGF和HGF訊號通路的抑制相一致。對於所有患者，暴露是與劑量成比例的，並在整個給藥期內持續(最多15個月)。半衰期約為2周。觀察到單藥抗腫瘤活性跡象：1例未確診部分緩解，進展時間23周，穩定期24例，最長持續72周，中位持續18周。

CONCLUSION 結論

MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies.

MP0250是首個DARPin候選藥物，具有適當的耐受性和適當的藥代動力學特性，可與其他抗癌療法結合進一步開發。