Abstract LB-193: Phase I study of safety, tolerability, pharmacokinetics, and pharmacodynamics of AMP-224 (B7-DC Fc fusion protein) in a regimen containing cyclophosphamide (CTX) in patients with advanced solid tumors.
Authors: LoRusso Patricia M. , Powderly John , Burris Howard A. , Kittaneh Muaiad , Grice Jessica , Smothers James F. , Brett Sara , Fleming Margaret , May Rena J. , Marshall Shannon , Devenport Martin , Pillemer Stanley , Pardoll Drew M. , Chen Lieping , Langermann Solomon , Infante Jeffrey 
Published: August 2014

Abstract
Background: AMP-224 is a recombinant Fc fusion protein that binds to the programmed death-1 (PD-1) receptor. This first-in-human study was designed to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) profile, pharmacodynamics (PD), and preliminary anti-tumor activity of AMP-224. Additional translational studies were incorporated to characterize MOA in patients and identify possible prognostic indicators and markers of response.
Methods: Cohorts of 3-6 eligible patients with advanced solid tumors received CTX on Day 0, followed by AMP-224 by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle in doses ranging from 0.3 to 30mg/kg. Following dose escalation, an expansion cohort is ongoing at 10 mg/kg in predominantly melanoma patients. Fresh pre-treatment biopsies were obtained from patients and evaluated via IHC for B7-H1 (PD-L1), PD-1, CD8 and CD4. PD testing performed throughout the study included serial blood samples to assess lymphocyte subsets, expression of PD-1 on T cells and changes in T cell effector function.
Results: 42 patients (83% melanoma), were treated in cohorts of 0.3mg/kg (n = 6); 1mg/kg (n=4); 3mg/kg (n = 4); 10mg/kg (n = 21); 30mg/kg (n = 6), mean age 56 years. Two dose-limiting toxicities were observed, 1 each at 10 mg/kg (infusion reaction) and 30 mg/kg (flu-like symptoms). Infusion reactions were common (61%) across all doses but manageable with pre-medications. Common treatment-related adverse events (all grades) were chills (54%), fatigue (34%) flushing (34%), nausea (32%), vomiting (29%), fever (27%), and headache (22%). No drug-related inflammatory adverse events were identified. Preliminary PK analysis showed that exposures of AMP-224 were linear, dose-proportional with no evidence of target mediated clearance or accumulation. PD assays confirmed PD-1 receptor targeting with specific reduction of PD-1HI CD4 and PD-1HI CD8 T cells in a dose dependent manner. B7-H1+ tumors were found in fresh pre-treatment tumor biopsies in 31.4% of patients, yet B7-H1 expression within the tumor did not predict AMP-224 clinical activity. The trial is ongoing and the preliminary evaluation of clinical activity suggests individual patients with partial response, stable disease, and mixed response.
Conclusions: AMP-224 was well-tolerated up to its maximally administered dose of 30mg/kg, with manageable infusion reactions in the majority of patients. The trial is ongoing including monitoring for clinical activity.
Citation Format: Patricia M. LoRusso, John Powderly, Howard A. Burris, Muaiad Kittaneh, Jessica Grice, James F. Smothers, Sara Brett, Margaret Fleming, Rena J. May, Shannon Marshall, Martin Devenport, Stanley Pillemer, Drew M. Pardoll, Lieping Chen, Solomon Langermann, Jeffrey Infante. Phase I study of safety, tolerability, pharmacokinetics, and pharmacodynamics of AMP-224 (B7-DC Fc fusion protein) in a regimen containing cyclophosphamide (CTX) in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-193. doi:10.1158/1538-7445.AM2013-LB-193