Phase I and Pharmacokinetic Study of CT-322 (BMS-844203), a Targeted Adnectin Inhibitor of VEGFR-2 Based on a Domain of Human Fibronectin

Abstract

Purpose: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain-based targeted biologic (Adnectin) to enter clinical studies.Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies.Results: Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti-CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease.Conclusions: CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics.

Shark variable new antigen receptor biologics – a novel technology platform for therapeutic drug development

“…CT-322 (Angiocept) is the first engineered adnectin developed by Adnexus/Bristol-Myers Squibb and is an antagonist of VEGFR-2. CT-322 is currently in Phase II clinical trials for treatment of glioblastoma having completed Phase I studies without any significant adverse effects and with promising anti-tumour effects seen in some patients [100,101].…”

Phase 2 study of CT-322, a targeted biologic inhibitor of VEGFR-2 based on a domain of human fibronectin, in recurrent glioblastoma

“…The initial CT-322 dose for Part 2 was 1 mg/kg weekly. While Part 2 was ongoing, clinical data from a phase 1 of CT-322 study became available indicating that the maximum tolerated dose of CT-322 was 2 mg/kg weekly [9]. Consequently, the protocol was amended with enrollment into the initial randomized arms of Part 2 (Arms A and B) suspended, and a 2 mg/kg safety lead-in commenced with enrollment into Cohorts 3 and 4.…”

A Novel Engineered Anti-CD20 Tracer Enables Early Time PET Imaging in a Humanized Transgenic Mouse Model of B-cell Non-Hodgkins Lymphoma

“…High stability and a single-lysine distant from the paratope ease amine conjugation of radioisotopes. In addition to preclinical molecular positron emission tomography (PET) validation, an engineered FN3 is in phase II for therapeutic oncology (28).…”