Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors

Abstract

Introduction

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.

Materials and 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.

ClinicalTrials.gov Identifier

NCT03724890.

Highlights

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  Genomic instability induced by the disruption of DNA damage response pathways can increase sensitivity to immunotherapies.

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  Peposertib, a DNA-dependent protein kinase inhibitor, had preclinical antitumor efficacy in combination with radiotherapy.

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  We assessed the safety and antitumor activity of peposertib + avelumab ± radiotherapy in advanced solid tumors.

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  Peposertib was well tolerated at doses ≤200 mg b.i.d. with avelumab and ≤250 mg q.d. with avelumab + radiotherapy.

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  Peposertib + avelumab ± radiotherapy had limited clinical activity.