背景:我们报告了第一阶段的结果,三部分,peposertib的剂量递增研究,DNA依赖性蛋白激酶抑制剂,与阿维鲁单抗联合使用,一种免疫检查点抑制剂,晚期实体瘤患者有或没有放疗。
方法:Peposertib100-400mg每天两次(b.i.d.)或100-250mg每天一次(q.d.)与阿维鲁单抗每2周800mg联合给药。部分B.部分评估了食物对peposertib加阿维鲁单抗药代动力学的影响。A部分和B部分的主要终点是剂量限制性毒性(DLT)。次要终点是安全性,根据RECIST1.1版的最佳总体反应和药代动力学。在A部分和B部分中确定了推荐的II期剂量(RP2D)和最大耐受剂量(MTD)。
结果:在A部分中,peposertib给药剂量为100mg(n=4),200毫克(n=11),250毫克(n=4),300毫克(n=6),和400mg(n=4)b.i.d.DLT可评估患者,1例患者的DLT分别为250mg和300mg剂量水平,3例患者的DLT分别为400mgb.i.d.剂量水平.在B部分,peposertib给药剂量为100mg(n=3),150毫克(n=3),200毫克(n=4),和250mg(n=9)q.d.;在可评估的患者中未报告DLT。Peposertib200mgb.i.d.加上avelumab和peposertib250mgq.d.加上avelumab和放射疗法被宣布为RP2D/MTD。A部分或B部分未观察到客观反应;一名患者在FE部分有部分反应。Peposertib暴露通常与剂量成正比。
结论:Peposertib剂量高达200mgb.i.d.与avelumab联合使用以及高达250mgq.d.联合使用avelumab和放疗在晚期实体瘤患者中是可以耐受的;然而,抗肿瘤活性有限。
结果:
■NCT03724890。
BACKGROUND: We report results from a phase I, three-part, dose-escalation study of
peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or without radiotherapy in patients with advanced solid tumors.
METHODS: Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of
peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B.
RESULTS: In Part A,
peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients.
Peposertib 200 mg b.i.d. plus avelumab and
peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE.
Peposertib exposure was generally dose proportional.
CONCLUSIONS: Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited.
RESULTS: UNASSIGNED: NCT03724890.