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.

• Authors: Carlos R Becerra, Paul Conkling, Nicholas Vogelzang, Hilary Wu, Shengyan Hong, Rajesh Narwal, Meina Liang, Fatemeh Tavakkoli, Naimish Pandya
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 74 Issue 5 Pg. 917-25 (Nov 2014) ISSN: 1432-0843 [Electronic] Germany
• PMID: 25149088 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Antibodies, Monoclonal, Humanized
• Tovetumab
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Cohort Studies
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Fatigue (chemically induced)
• Female
• Humans
• Male
• Metabolic Clearance Rate
• Middle Aged
• Nausea (chemically induced)
• Neoplasms (drug therapy, metabolism, pathology)
• Receptor, Platelet-Derived Growth Factor alpha (immunology)
• Survival Analysis
• Treatment Outcome
• Vomiting (chemically induced)