8PD - Phase I JAVELIN solid tumor trial of avelumab (MSB0010718C), an anti-PD-L1 antibody: Safety and pharmacokinetics

Date 20 November 2015
Event ESMO Symposium on Immuno-Oncology 2015
Session Poster Discussion session
Topics Immunotherapy
Therapy
Presenter Henrik-Tobias Arkenau
Citation Annals of Oncology (2015) 26 (suppl_8): 1-4. 10.1093/annonc/mdv513
Authors H. Arkenau1, K. Kelly2, M.R. Patel3, B. Neuteboom4, I. Speit5, K. Chin6, C.R. Heery7, J.L. Gulley8
  • 1Drug Development Unit, Sarah Cannon Research Institute, W1G 6AD - London/UK
  • 2Department Of Hematology And Oncology, University of California-Davis Comprehensive Cancer Center, Sacramento/US
  • 3Medical Oncology, Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota/US
  • 4Quantitative Pharmacology And Drug Disposition Department, EMD Serono, Inc, Billerica/US
  • 5Global Drug Safety, Merck KGaA, Darmstadt/DE
  • 6Research & Development Institute, EMD Serono, Inc, Billerica/US
  • 7Laboratory Of Tumor Immunology And Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda/US
  • 8Laboratory Of Tumor Immunology And Biology, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda/US

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.

Treatment-related TEAEs, n (%) Dose-escalation (n = 53) Dose-expansion (n = 600)
All grades 43 (81.1) 405 (67.5)
Grade ≥3 9 (17.0) 68 (11.3)
Leading to discontinuation 7 (23.2) 41 (6.8)
Grade 5 0 5 (0.8)

Clinical trial identification

NCT01772004

Disclosure

K. Kelly: Consulting/advisory role: Synta, Daiichi-Sankyo, Boehringer-Ingelheim, Genentech, Clovis, Lilly, Transgene. Research funding: Millennium, Novartis, Proacta, Lilly, Synta, EMD Serono, Genentech. Patents, royalties, other intellectual property: UpToDate. B. Neuteboom and K. Chin: Are employees of EMD Serono, Inc., Billerica, Massachusetts, a subsidiary of Merck KGaA, Darmstadt, Germany. I. Speit: Is an employee of Merck KGaA, Darmstadt, Germany. J.L. Gulley: Honoraria: TRM Oncology. All other authors have declared no conflicts of interest.