Phase I JAVELIN solid tumor trial of avelumab (MSB0010718C), an anti-PD-L1 antibody: Safety and pharmacokinetics

Abstract

Aim: Avelumab∗ (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in multiple clinical trials. We report safety, pharmacokinetic (PK) profile, and target occupancy (TO) data from a phase I trial in patients ( pts) with advanced solid tumours. Methods: Dose escalation (3 + 3 design) was performed for 4 dose levels (DL; 1, 3, 10, and 20 mg/kg). The dose limiting toxicity (DLT) evaluation period was 3 wks. After DL safety was determined, additional pts were accrued to assess safety, PK, and TO. Binding of avelumab to PD-L1 on leukocytes was investigated by flow cytometry. Pts unselected for PD-L1 expression received avelumab Q2W by IV infusion until confirmed progression, unacceptable toxicity, or withdrawal. Tumours were assessed every 6 wks (RECIST 1.1). Adverse events (AEs) were graded by NCI-CTCAE v4.0. Results: As of 13 Jan 2015, 53 pts in the dose-escalation part and 600 pts in the dose-expansion part were treated. Treatment-related (TR-), treatment-emergent AEs (TEAEs) are shown in table. One DLT was reported (immune-related) at the 20-mg/kg dose. The 10-mg/kg dose was selected for dose-expansion, in which the most common (>10%) all-grade TR-TEAEs were fatigue (n = 110, 18.3%), infusion-related reactions (IRRs; n = 81, 13.5%), and nausea (n = 68, 11.3%). The 3 most common grade ≥3 TR-TEAEs were anaemia (n = 7, 1.2%), fatigue (n = 5, 0.8%), and IRRs (n = 5, 0.8%). The mean half-life of avelumab at 10-mg/kg was 102 ± 26h (SD), Cmax was 301 ± 102 μg/mL, and Cmin was 22 ± 12 μg/mL. The PK profile was linear over the dose range, a 2-compartment model best fit the population PK data, and TO was >95% over the whole 2-wk dosing period at 10 mg/kg. Conclusions: Avelumab showed an acceptable safety profile, a predictable PK profile, and full TO over the dosing period. Clinical activity and PD-L1 expression analyses are ongoing. ∗Proposed INN. (Table Presented).