First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors.
Shapiro GI1, Vaishampayan UN2, LoRusso P3, Barton J4, Hua S4, Reich SD4, Shazer R4, Taylor CT5,6, Xuan D4, Borghaei H7. Author information 1 Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Mayer 446, Boston, MA, 02215, USA. geoffrey_shapiro@dfci.harvard.edu. 2 Karmanos Cancer Institute, Detroit, MI, USA. 3 Yale University, New Haven, CT, USA. 4 Pfizer Oncology, La Jolla, CA, USA. 5 Pfizer Oncology, La Jolla, CA, USA. Carrie.Taylor@pfizer.com. 6 Pfizer Early Oncology Development and Clinical Research, 10777 Science Center Drive, CB-1, San Diego, CA, 92121, USA. Carrie.Taylor@pfizer.com. 7 Fox Chase Cancer Center, Philadelphia, PA, USA. 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.
