A phase I dose-escalation study of MEDI-575, a PDGFRα monoclonal antibody, in adults with advanced solid tumors

Abstract

Purpose: The purpose of the study was to evaluate safety and determine the maximum tolerated dose (MTD) of MEDI-575, a fully human monoclonal antibody that selectively binds to platelet-derived growth factor receptor-α (PDGFRα), in patients with advanced solid tumors.

Methods: This phase I multicenter, open-label, single-arm study enrolled adults in a 3 + 3 dose escalation design to receive MEDI-575 (3, 6, 9, 12, or 15 mg/kg) once weekly (QW) until toxicity or disease progression occurred. One 0.5-mg/kg dose was given before the first dose in the 3-mg/kg cohort to determine pharmacokinetics (PK) and pharmacodynamics under unsaturated conditions. After completion of dose escalation in the QW cohorts, patients were enrolled in two additional cohorts and received MEDI-575 25 or 35 mg/kg every 3 weeks (Q3W). Secondary measures included assessments of PK, immunogenicity, and antitumor activity.

Results: A total of 35 patients received MEDI-575 QW (n = 23) or Q3W (n = 12). Most treatment-related adverse events were grade 1 or 2 in severity across all dose levels, with fatigue (n = 12) and nausea (n = 8) being reported most frequently. With no reports of dose-limiting toxicities (DLTs), the MTD was not reached. MEDI-575 exhibited a nonlinear PK profile and increased plasma platelet-derived growth factor-AA levels in a dose-dependent manner with limited immunogenicity. Stable disease was reported as the best tumor response in 9 of 29 evaluable patients; however, no objective responses were reported.

Conclusion: Administration of MEDI-575 QW or Q3W resulted in a favorable safety profile, including a lack of DLTs, but without evidence of antitumor activity in patients with refractory solid tumors.

Trial registration: ClinicalTrials.gov NCT00816400.

Figures

Fig. 1

Dose escalation study design. The dose expansion phase included two additional cohorts dosed at either 9 mg/kg weekly or 25 mg/kg every 3 weeks. *Patients enrolled in dose cohort 1 received a single lead-in dose of MEDI-575 at 0.5 mg/kg on day 1 (7 days prior to receipt of the first dose of MEDI-575 3 mg/kg on day 8)

Fig. 2

Pharmacokinetic and pharmacodynamic effects of MEDI-575. Mean a MEDI-575 serum concentration–time profiles and b PDGF-AA plasma concentration–time profiles following weekly and every 3 week dosing regimens of MEDI-575. PDGF platelet-derived growth factor, QW once weekly; Q3W every 3 weeks