First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors

Geoffrey I Shapiro, Ulka N Vaishampayan, Patricia LoRusso, Jeremy Barton, Steven Hua, Steven D Reich, Ronald Shazer, Carrie T Taylor, Dawei Xuan, Hossein Borghaei, Geoffrey I Shapiro, Ulka N Vaishampayan, Patricia LoRusso, Jeremy Barton, Steven Hua, Steven D Reich, Ronald Shazer, Carrie T Taylor, Dawei Xuan, Hossein Borghaei

Abstract

Background The antibody-drug conjugate PF-06263507 targets the cell-surface, tumor-associated antigen 5T4 and consists of a humanized IgG1 conjugated to the microtubule-disrupting agent monomethylauristatin-F by a non-cleavable maleimidocaproyl linker. In this first-in-human, dose-finding trial (NCT01891669), we evaluated safety, pharmacokinetics, and preliminary antitumor activity of PF-06263507 in pretreated patients with advanced solid tumors, unselected for 5T4 expression. starting at 0.05 mg/kg, with 25, 56, and 95% dose increments, depending on observed dose-limiting toxicities (DLTs), applying a modified continual reassessment method. Results Twenty-six patients received PF-06263507 at 0.05 to 6.5 mg/kg. The first DLT, grade 3 photophobia, occurred at 4.34 mg/kg and two additional DLTs, grade 2 keratitis and grade 1 limbal stem cell deficiency (> 2-week dosing delay), at 6.5 mg/kg. The most common adverse events (AEs) were fatigue (38.5%), photophobia (26.9%), and decreased appetite, dry eye, nausea, and thrombocytopenia (23.1% each). No treatment-related grade 4-5 AEs were reported. Systemic exposure of PF-06263507 increased in a dose-related manner. At the maximum tolerated dose (MTD, 4.34 mg/kg), mean terminal half-life for PF-06263507 and unconjugated payload were ~6 and 3 days, respectively. Payload serum concentrations were substantially lower compared with PF-06263507. No objective responses were observed. Conclusions The MTD and recommended phase II dose were determined to be 4.34 mg/kg. Ocular toxicities accounted for the DLTs observed, as previously reported with monomethylauristatin-F payloads. Further studies are warranted to investigate clinical activity of this agent in patients with 5T4-expressing tumors.Trial registration ID: NCT01891669.

Keywords: 5T4; Antibody-drug conjugate; Immunoconjugate; Monomethylauristatin conjugate; PF-06263507; Solid tumors.

Conflict of interest statement

Conflict of interest

G. I. Shapiro received research funding from Pfizer. U. N. Vaishampayan has nothing to disclose related to this study. P. LoRusso received an advisory board honorarium from Pfizer. H. Borghaei received research funding from Takeda (Millennium), Merck, and Celgene; and consulting honoraria from BMS, Lilly, Genentech, Pfizer, Celgene, Boehringer-Ingelheim, Trovogene, and EMD-Serono. J. Barton, S. Hua S, R. Shazer R, C. T. Taylor, and D. Xuan were employees of Pfizer during the conduct of this study. S. D. Reich is a contractor for Pfizer.

Research involving human participants

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Structure of PF-06263507
Fig. 2
Fig. 2
Mean serum concentration-time profiles (semi-log scale) of PF-06263507, PF-06281192, and PF-06264490 following a single 4.34 mg/kg intravenous infusion of PF-06263507 (cycle 1)

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