Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors

• Published in: Clinical cancer research Vol. 22; no. 4; pp. 827 - 836
• Main Authors: Patnaik, Amita, Weiss, Glen J., Leonard, John E., Rasco, Drew Warren, Sachdev, Jasgit C., Fisher, Terrence L., Winter, Laurie A., Reilly, Christine, Parker, Robert B., Mutz, Danielle, Blaydorn, Lisa, Tolcher, Anthony W., Zauderer, Maurice, Ramanathan, Ramesh K.
• Format: Journal Article
• Language: English
• Published: United States 15.02.2016
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Area Under Curve; Colonic Neoplasms - drug therapy; Disease-Free Survival; Female; Humans; Male; Middle Aged; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-0431

Purpose: Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VX15/2503 in advanced solid tumor patients. Experimental Design: Weekly i.v. doses were administered on a 28-day cycle. Safety, immunogenicity, PK, efficacy, T-cell membrane–associated SEMA4D (cSEMA4D) expression and saturation, soluble SEMA4D (sSEMA4D) serum levels, and serum biomarker levels were evaluated. Results: Forty-two patients were enrolled into seven sequential cohorts and an expansion cohort (20 mg/kg). VX15/2503 was well tolerated. Treatment-related adverse events were primarily grade 1 or 2 and included nausea (14.3%) and fatigue (11.9%); arthralgia, decreased appetite, infusion-related reaction, and pyrexia were each 7.3%. One pancreatic cancer patient (15 mg/kg) experienced a Grade 3 dose-limiting toxicity; elevated γ-glutamyl transferase. Complete cSEMA4D saturation was generally observed at serum antibody concentrations ≥0.3 μg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusion number. Neutralizing anti-VX15/2503 antibodies led to treatment discontinuation for 1 patient. VX15/2503 Cmax and AUC generally increased with dose and dose number. One patient (20 mg/kg) experienced a partial response, 19 patients (45.2%) exhibited SD for ≥8 weeks, and 8 (19%) had SD for ≥16 weeks. Subjects with elevated B/T lymphocytes exhibited longer progression-free survival. Conclusions: VX15/2503 was well tolerated and produced expected PD effects. The correlation between immune cell levels at baseline and progression-free survival is consistent with an immune-mediated mechanism of action. Future investigations will be in combination with immunomodulatory agents. Clin Cancer Res; 22(4); 827–36. ©2015 AACR.